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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5344_Библиотеки_им_академика_М_И_Перельмана.pdf
Introduction to Pharmaceutical Biotechnology, Volume 2 (Second Edition)
aspects of DNA methylation patterns. Histone modifications play a pivotal role in the
regulation of genome functionality. They consist of post-translational modifications
(PTMs) such as acetylation, phosphorylation, methylation, ubiquitination, and
ADP ribosylation, which are carried out on the amino acid residues of histone
proteins. These modifications can lead to a condensed or relaxed chromatin
structure, thereby regulating gene expression. For instance, acetylation generally
results in a more relaxed chromatin structure and, thus, enhanced gene expression.
Furthermore, histone modifications can also have carcinogenic potential, with
abnormal modification sites observed in various tumors. Some of these modifications are studied extensively, while others have been recently discovered, reflecting
the complexity and ongoing research in understanding histone PTMs and their
mechanistic implications in diseases like cancer [76]. Non-coding RNAs (ncRNAs)
are instrumental in epigenetic regulation. They function in chromatin remodeling
and regulation at both transcriptional and post-transcriptional levels. They modulate gene expression by interacting with other molecular entities like microRNA
pathways, influencing various cellular processes. These ncRNAs play a role in
vascular biology and mediate epigenetic modifications related to cardiovascular
disease susceptibility [77]. Moreover, ncRNAs are key epigenetic factors that
modulate cellular fate and gene expression patterns, thus playing a crucial role in
the broader landscape of epigenetic regulation. The workflow of epigenetic regulation of gene expression is shown in figure 7.15.
7.12.1 Epigenetic inheritance and diseases
Epigenetic inheritance involves the transmission of gene expression patterns across
generations lacking amendments in the DNA chain. There is a suggestion that
Figure 7.15. Epigenetic regulation of gene expression: interplay of histone modifications and DNA methyl-
ation in chromatin remodeling and RNA transcription.
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epigenetic modifications triggered by environmental variables may influence the
inheritance of illness vulnerability. These epigenetic alterations encompass DNA
methylation, chromatin remodeling, histone modifications, and the activity of
ncRNAs, all of which can lead to heritable phenotypic changes [78]. The disruption
of gene expression patterns governed by epigenetics can result in various diseases,
including autoimmune diseases and cancers. Moreover, epigenetics plays a significant role in disease etiology and understanding it better could unveil novel strategies
for diagnosis and treatment of diseases. Some diseases are associated with mutations
and epimutations in genes subject to genomic imprinting, a form of epigenetic
regulation [79].
7.13 Pharmacogenomics
Pharmacogenomics is an interdisciplinary science that blends the principles of
pharmacology and genomics to explore how an individual’s genetic make-up
influences their response to drugs. This field holds the promise of personalized
medicine, where therapeutic strategies are tailored to everyone based on their genetic
profile. Pharmacogenomics endeavors to understand the genetic underpinnings
contributing to individuals’ varied responses to drugs, encompassing efficacy and
adverse effects [80]. This study examines the relationship between drugs and the
genome, specifically investigating the impact of genetic variations, such as SNPs and
copy number variations (CNVs), on drug absorption, distribution, metabolism, and
excretion (ADME) processes. Additionally, it explores the influence of genetic
variations on drug targets, including receptors and enzymes. Pharmacogenomics has
advanced a long way from its infancy; the first pharmacogenomic recommendations
for dosage had been released before the human genome was sequenced. The
progression of pharmacogenomics in contemporary medicine has been characterized
by the emergence of increasingly extensive dosage recommendations and genotyping
technologies [81]. This evolution underscores the rapid growth and promise of
pharmacogenomics in the field. Pharmacogenomics has a substantial influence on
the realm of clinical practice. By knowing how genes affect drug response, doctors
can choose the right drug in the right amount for each patient. This improves
treatment results, lowers the risk of side effects, and improves patient care.
Variations in drug metabolism are a clinically significant example because they
can change how well or how dangerously a drug works [82].
7.13.1 The importance of personalized medicine
Personalized medicine encompasses a customized methodology that considers the
unique interplay of genetic factors, environmental influences, and individual lifestyle
choices for every individual. This idea aims to maximize the effectiveness of
therapies while minimizing adverse side effects. In personalized medicine, the study
of how a person’s genes influence their reaction to medications is known as
pharmacogenomics. This helps doctors craft individualized treatment plans for their
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Figure 7.16. Influence of genetic polymorphisms on drug response: a schematic overview of pharmacokinetic
and pharmacodynamic variations.
patients, improving care quality, safety, and the likelihood of positive outcomes [83].
The genetic polymorphisms on drug response overflow is shown in figure 7.16.
7.13.2 The impact of genetic variations on drug response
The observed disparities in medication responses among human populations can be
attributed to the substantial influence of genetic variants. The discipline of
pharmacogenomics aims to establish a correlation between genetic diversity and
the variety observed in medication response. The focus of research in this field has
transitioned from candidate gene studies to investigations of genetic diversity across
entire genomes of human populations, encompassing individuals who display
diverse responses to drugs [84]. The significance of genetic variants in drugmetabolizing enzymes is particularly pronounced, underscoring the necessity of
incorporating both genotype and medication interaction data to enhance clinical
results, particularly in neurology and psychiatry. Moreover, genetic variations can
affect drug-related genes. For instance, a focused analysis revealed that the likelihood of a patient carrying germline variants in oncological drug targets is high
enough to suggest that somatic alterations and germline variants could influence the
response to antineoplastic agents [85].
7.13.3 Additional insights on pharmacogenomics
Pharmacogenomics, an evolving clinical tool for precision medicine, studies how an
individual’s genomic profi le influences drug response. It aids in optimizing drug
therapy by helping in drug selection and dosing, thereby reducing the risk of severe
adverse effects from certain drugs. The field has rapidly developed, with the first
pharmacogenomics dose recommendations published before human genome
sequencing. This rapid evolution has brought about more comprehensive dosing
guidelines and genotyping technologies, underlining pharmacogenomics’s expansion
and potential in modern medicine [86].
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7.13.4 Pharmacogenomic tests in the market
Pharmacogenomic tests are designed to evaluate a person’s genetic make-up to
predict how they might metabolize or respond to medications, which is crucial in
guiding healthcare providers in choosing the proper medications and dosing for
individuals. These tests mainly include pharmacokinetic and pharmacodynamic
genomic panels, which analyze how one’s body affects a drug and how drugs affect the
body, respectively. Pharmacogenomic testing is implemented in specialist academic
centers worldwide, adopting a preemptive panel approach where patients are tested for
multiple pharmacognosies on admission, and the results are integrated into the
patient’s electronic health records. Pharmacogenomic testing aims to maximize
medication benefits while minimizing unintended adverse drug reactions by detecting
genomic factors linked to drug response variability before treatment [87].
7.13.5 Challenges in implementing pharmacogenomics
The challenges in implementing pharmacogenomics are substantial and can be
categorized broadly into two aspects. The first revolves around whether the testing
should be performed, which relates to the sufficiency of available evidence and costeffectiveness. The second pertains to integrating pharmacogenomic testing into
clinical systems and workflows. One of the significant hurdles lies at the point of
delivery into healthcare systems, requiring the modification of current clinical
pathways and bridging a significant knowledge gap. The implementation challenges
extend to the clinical practice setting, where there is a need for a clear understanding
of how pharmacogenomic testing impacts clinical practices. In developing countries,
identifying and overcoming challenges related to pharmacogenomics implementation,
especially considering the experiences of early adopters and local experts, is crucial.
Pharmacogenetic implementation initiatives are continuously explored, focusing on
overcoming these challenges to improve drug safety and effectiveness [88].
7.14 Population genomics
Population genomics is a branch of genetics that analyses and compares genomic
sequences within and across populations to understand genetic diversity, evolution,
and the molecular basis of heritable traits and diseases. Population genomics takes a
more comprehensive approach by analyzing the complete genomes of many people
from various populations instead of studying individual genes or small sets of genes,
as is common in classical genetics. The discipline of population genomics is
primarily concerned with examining the effects of genetic diversity on the range
of observable traits within populations while also seeking to comprehend the
evolutionary processes that have shaped this diversity throughout time [89]. Using
the concepts of population genetics on a genomic scale deepens our understanding of
evolutionary processes, genetic adaptation, and the underlying genetic architecture
of complex features. Evolution, biological conservation, and medicinal research may
all benefit from population genomics due to its applicability across a wide range of
species. Breakthroughs in technology, such as the development of technology for
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sequencing of the next generation (NGS), have significantly impacted the progression of population genomics. These technical developments have facilitated the
generation of large volumes of genomic data at an economically feasible cost,
enabling thorough exploration of genetic diversity on a vast scale. Using long-read
sequencing technology has dramatically improved the detection of structural
alterations, a common form of genetic diversity within species [90].
7.14.1 Studying genetic variation across populations
Understanding human evolution, migration patterns, and the genetic basis of
diseases requires researching the genetic differences that exist across different
populations. The examination of genetic diversity and allele frequencies across
various populations worldwide is a fundamental application within the area of
population genomics. This specialized branch of population genetics utilizes
genomic data to achieve its objectives. This work is of great importance in
examining evolutionary alterations, as shown by the analysis of population genetics,
including 103 genomes of SARS-CoV-2. Even though the repercussions of these
evolutionary shifts are still being researched, one study has demonstrated the
presence of two fundamental lineages. Improved knowledge of evolution inheritance, molecular ecology, and biodiversity conservation may be achieved via
population genomics, which identifies adapted molecular variation [91].
7.14.2 Population genomics techniques
Population genomics has seen significant progress, mainly due to the emergence of
NGS technology. These tools have made a big difference in the field by letting
scientists learn more about genome structure variation, the primary type of genetic
diversity within species. For example, advances in long-read sequencing technology
have made it easier to find structural changes, which has improved our ability to
characterize the genetic landscape of different populations. Moreover, various
analytical methods are employed to handle and interpret the voluminous data
generated through genomic studies [92]. Zhang et al (2020) mention that multiple
approaches must be used and compared in any population genomics project,
underscoring the complexity and the multi-dimensional nature of the analyses
required in population genomics [93].
7.14.3 Understanding human migration and evolution through population genomics
Population genomics provides a comprehensive lens through which human migration and evolution can be investigated. Established population genetics principles,
applied with the advent of human genome sequencing projects, reveal intricate
migration histories and population structures, especially in smaller ethnic populations. The dispersion of different human communities globally led to exposure to
various infectious agents, hence creating a selection pressure that favored the
adaptation to new environments by selecting beneficial genetic variants for the
host. Advances in genomic sequencing and statistical analysis are now unveiling the
links between past human migrations and present-day genetic differences governing
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traits like disease resistance, skin pigmentation, and tolerance to different environmental conditions [94]. The examination of genomic data derived from contemporary and historical populations enhances comprehension of genealogical
connections, patterns of migration, instances of diversification, and genetic intermingling among diverse groups, augmenting our understanding of humanity’s
evolutionary history [95].
7.14.4 Conservation genomics in endangered species
The subject of conservation genomics is experiencing significant growth, utilizing
genome-scale data to augment the abilities of resource managers in safeguarding
species. Genetic methodologies have been extensively employed in the field of
conservation research. The advent of genomics has facilitated the collection of
extensive genome-wide information, which plays a pivotal role in efforts to preserve
biodiversity. The field of advanced genomics encompasses a range of applications
that contribute to the conservation of endangered species. These applications include
studying demographic patterns, adaptive genetic variants, inbreeding, hybridization,
introgression, and illness vulnerabilities in vulnerable biota. The investigation of
threatened species’ genomes that had previously been limited to the study of model
organisms has become possible because of recent developments in genomics [96].
NGS methodologies and the collection of genome-wide data provide more extensive
examinations of genetic diversity, population organization, and other crucial
variables in species under threat. Furthermore, genetics is essential to finding
‘conservation priors,’ which are already set goals to help threatened species or
groups that need to be saved immediately. This gives conservation plans a stronger
foundation. The enhanced understanding of the genome composition and variability
in endangered species has significant implications for population assessment,
surveillance, administration, and the comprehension of phylogeography. These
advancements can significantly contribute to managing wildlife health, identifying
genetic disorder risk factors, and developing strategies for the demographic management of small populations in their natural habitats [97].
7.15 Microbiome genomics
The study of microorganisms or colonies of microorganisms found in a variety of
habitats, such as the human body, has given rise to the multidisciplinary area of
microbiota genomics. This discipline focuses on comprehending the interactions
between microbial genomes, their host organisms, and their surrounding environment. This research uses a range of genomic methodologies to investigate the
diversity, functionality, and dynamics of microorganisms at a genomic level. The
expertise gained from gut microbiome genomics significantly improves our comprehension of how microbes coevolve, the diversity of microbes at the strain level,
and the connections between specific genomic changes in the microbiome and
common metabolic diseases, especially when it comes to human health [98].
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7.15.1 Introduction to the human microbiome
The phrase ‘human microbiome’ refers to the vast community of microorganisms,
such as bacteria, viruses, fungi, and other microbes, living inside and colonizing the
human body. Microbial communities are of utmost significance in human health
and illness. The bacteria under consideration possess a substantial amount of genetic
material, as shown by calculations that propose a range of 2–20 million microbial
genes associated with the human body. This amount is much higher than the roughly
20 000 human genes by a ratio of at least 1000-fold higher. The microbiome of
humans is sometimes called the ‘second genome’ because of its substantial influence
on our physiology and overall wellbeing [99]. The liver plays a crucial role in several
vital processes, such as digestion, synthesis of nutrients, control of immunity, and
defence against harmful microorganisms. It has also been shown that changes in the
make-up and function of the human microbiome are associated with several
metabolic diseases. The metagenome is the aggregate word for the genomes of
these many microbial communities. It symbolizes the microbial genomic contribution to the mammalian halobiont, which is generated by the host and its microbial
communities [100]. Recent technological advancements, specifically in NGS and
metagenomics, have facilitated comprehensive investigation and comprehension of
the human microbiome. This has provided an avenue for unraveling the intricate
interplay between the host and its microbiome and the potential ramifications of
these interactions on human health [101].
7.15.2 Techniques in studying microbial communities
Many different molecular approaches and sequencing methods are used to investigate microbial populations. One noteworthy methodology among these various
approaches is NGS, which has demonstrated its efficacy in analyzing microbial
populations through sequencing specific DNA targets. For instance, 16S ribosomal
RNA gene amplified products can be sequenced to study bacterial populations, while
the interior translated gap zones of ribosomal RNA genes can be sequenced to
investigate fungal populations. Additionally, metagenomics can be employed using a
shotgun approach to study viral populations. Fluorescence in situ hybridization FISH2 is another molecular biological method that might be utilized to study microbes in
anaerobic digesters. Additionally, new developments in molecular PCR-based methods have been discussed as a useful way to fully examine microbial communities,
focusing on finding out their variety, identification, and abundance [102].
7.15.3 Role of microbiome in human health and disease
The human microbiome is critical in determining health and disease states. It
comprises many organisms, such as bacteria, archaea, viruses, and eukaryotes, all
playing essential roles in the body’s metabolic and immunological processes. The
microbiome plays a crucial role in digestion, acts as a protective barrier against
harmful pathogens, contributes to the maturation of the immune system, and
establishes communication with intestinal cells to uphold the overall wellbeing of
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the gastrointestinal tract. Disturbances in the microbiome have been linked to
various ailments, including cancers and autoimmune and cardiovascular diseases.
The composition of the gut microbiota, influenced by diet, stress, and medication,
plays a significant role in health and disease [103].
7.15.4 Environmental microbiomes and their importance
Environmental microbiomes, comprising the microbiomes in the surroundings and
those of animals in close contact, significantly impact the human microbiome and
health outcomes. Microbiome transfer can occur in various settings like households
and workplaces, affecting both the human microbiome and health. Environmental
microorganisms, such as nitrogen, phosphorous, and carbon, play crucial roles in
biochemical cycles, are central to Earth’s systems and cycles. They adapt to external
changes and are essential to agricultural practices, providing solutions to everyday
needs through applied microbiology [104].
7.16 Synthetic biology and genome editing
Synthetic biology and genome editing are intertwined fields that blend engineering
principles with biological systems to create novel functionalities or modify existing
ones. Synthetic biology focuses on designing new biological parts, devices, or
systems, embodying a modular and standardized approach that facilitates the
creation of organisms with desired traits for applications in medicine, environmental
remediation, and industrial processes. In contrast, genome editing encompasses the
meticulous alteration of an organism’s DNA via advanced technologies such as
CRISPR-Cas9, ZFNs, TALENs, and base editing. This technique has enabled the
treatment of genetic illnesses, the generation of genetically enhanced crops, and the
engineering of microbes for use in various industrial applications. It has also opened
new vistas in the field of medical research as well as agriculture and biotechnology.
Despite ethical, technological, and accessibility concerns, both professions show
potential in tackling some of society’s most intractable problems [105]. As a field of
study, synthetic biology combines ideas and methods from engineering and biology
to create new living systems or change existing ones. The notion encompasses a wide
array of strategies, technologies, and processes, intending to create customized
solutions in several sectors like healthcare, industry, and the environment.
These are some key principles of synthetic biology and genome editing:
• Modularity: This views biological systems as discrete, interchangeable, and
reusable components.
• Standardization: The standardization of biological components promotes
uniformity and repeatability, allowing more people to share components
and design ideas.
• Abstraction: It simplifies complex biological systems into understandable and
manageable layers or modules.
• Metabolic engineering: Customizing microbial metabolic pathways to pro-
duce desired substances like biofuels or pharmaceuticals.
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• Gene circuits: Designing gene circuits to control cellular behaviors
predictably.
• Genetic engineering: Modifying organisms’ genetic make-up to induce desired
traits or behaviors.
• Medicine: Developing new therapies, diagnostics, and drug delivery systems.
7.16.1 Techniques like CRISPR/Cas9 in genome editing
CRISPR/Cas9, discovered by Doudna and Charpentier in 2012, revolutionized
genome editing by providing a more effective, efficient, and accurate method to alter
DNA in living cells across various disciplines. This system originates from a
prokaryotic immune defence mechanism and has been adapted for genome editing
in many organisms. It operates by guiding an endonuclease, Cas9, to a specific DNA
sequence, which induces a double-strand break that can be repaired either imprecisely or precisely, enabling gene disruption or specific sequence alterations,
respectively [106]. Genome editing, mainly through CRISPR/Cas9, holds immense
promise across the biological fields: medical research aids in understanding, treating,
or even curing genetic diseases; tailoring crops for better yield, nutritional value, or
resistance to pests and diseases; engineering microorganisms for desired outputs like
biofuels or chemicals. However, it brings about ethical concerns, particularly in
human germline editing, which could have unforeseen consequences and raises
issues of consent, equity, and societal acceptance. The irreversible nature of genome
editing further emphasizes the need for careful consideration and robust regulatory
frameworks [107].
7.17 Systems biology and genomics
Systems biology encompasses various disciplines and aims to explore intricate
relationships and the collective dynamics occurring within a cell or an organism.
The primary objective of this study is to gain a comprehensive understanding of
biological systems, utilizing a wide array of methodologies that span from molecular
biology to computational modeling. The goal is to unveil the intricate networks of
interactions that drive biological processes and to develop an integrative understanding of how these interactions lead to the emergent properties observed in
biological systems. Genomics, on the other hand, is the study of the genome, the
complete set of DNA within a cell of an organism. It involves the sequencing and
analysis of genome structures and the identification of genes. Genomics provides the
raw material and often the initial insights that fuel investigations within systems
biology [108]. Genomics and systems biology are often intertwined; genomics
provides fundamental insights into the genetic basis of organisms, which systems
biology leverages to understand the complexity of biological systems. The utilization
of systems biology approaches, such as whole-genome sequencing, enhances the
comprehension of gene function, hence facilitating the advancement of techniques
for genetic manipulation. The interaction between genomics and systems biology is
known as systems genomics or genomic systems biology. This term signifies the
convergence of these two fields to leverage genetic data to gain insights into the
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underlying biological processes at the cellular or organismal levels [109].
Technological developments have significantly influenced the progression of systems
biology and genomics. Using methodologies such as genome sequencing, bioinformatics, and high-throughput experimentation has facilitated the acquisition of
extensive datasets. The datasets offer a thorough comprehension of intricate
biological systems, enhancing the advancement of systems and synthetic biology.
Automated DNA sequencing machines with high-throughput capabilities have
significantly diminished the temporal and financial burdens associated with bacterial
genome sequencing, expediting genomics research and its subsequent utilization in
systems biology [110]. The field of systems biology endeavors to create innovative
approaches for comprehensively understanding the functionality of biological
systems. This statement provides insight into how bacteria adapt, evolve, and
interact with other organisms. It also highlights the dynamics of RNAs, proteins,
and metabolites, illuminating their intracellular relationships and revealing intricate
regulatory networks. Synthetic biology, commonly regarded as a technological
complement to systems biology, centers on developing artificial tools to accomplish
specific functions. Microbes are particularly well-suited hosts for numerous essential
applications in synthetic biology, including bioremediation, biodegradation, bioconversion, and bioproduction. The utilization of knowledge derived from systems
biology informs the development of enhanced synthetic biology methods, facilitating
the integration of these two disciplines and promoting progress in diverse areas such
as energy, materials, and environmental applications [111]. In microbiology, there
has been a notable convergence between systems biology and synthetic biology in
recent times. As exemplified, engineered microorganisms have been widely
employed in producing medicinal proteins, industrial enzymes, tiny molecular
medicines, chemicals, biofuels, and materials. The utilization of synthetic biology
tools in investigating and manipulating genomics, transcriptomics, proteomics, and
metabolomics in microbial systems exemplifies the collaborative relationship
between systems biology and synthetic biology. This partnership suggests the
significant potential inherent in integrating these disciplines for studying and
engineering microbes to carry out complex functions, such as the production of
biofuels [112].
7.17.1 Integrative approaches in genomics
The goal of integrative genomics is to understand the intricate relationships that
exist within biological systems by combining information from a variety of genetic
datasets. It uses computational and statistical tools to analyse, interpret, and
visualize genomic data. The molecular processes behind illnesses and other biological phenomena may be better understood with the help of integrated analysis.
Methods include integrating information from numerous genomic datasets, such as
gene expression, copy number variation, and methylation data, to characterize a
biological system better. Multidisciplinary methods to comprehend the chemical
processes that underlie diseases and the relevance of computational instruments in
evaluating various genomic data [112].
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