Central Dogma of Biology

The central dogma of biology, initially proposed as a hypothesis by Francis Crick in 1957 and later popularized in a 1970 article in the journal "Nature," serves as a fundamental concept in understanding the flow of biological information within living organisms. Crick introduced the central dogma as a principle governing the transfer of sequential information at the molecular level.

In the opening lines of his paper, Crick stated, "The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred back from protein to either protein or nucleic acid." This concise statement outlines the directional flow of information in biological macromolecules: from DNA to RNA and from RNA to proteins.

However, in the realm of science, the term "dogma" may not accurately reflect the principles and nature of scientific inquiry.  According to Oxford dictionary Dogma means: “a belief or set of beliefs held by a group or organization, which others are expected to accept without argument” and Cambridge dictionary says:  “a fixed, especially religious, belief or set of beliefs that people are expected to accept without any doubts”. There is nothing such as this in all of the scientific fields. We do not have beliefs in science, we have experimental proof. The center of science is argument and doubts about the most basic things.

Although the term “central dogma of biology” is widely used in many contexts, it is important to note that it is not a scientific term in the strictest sense. Apparently, Francis Crick acknowledged that he used the term more as a catchphrase rather than a scientifically precise expression. In retrospect, he expressed his uncertainty about the true meaning of the word "dogma" and admitted that "central hypothesis" might have been a more suitable choice. Crick had reservations about adopting the term, even stating that it wasn't worth the trouble, and the reason he did not use “central hypothesis” was because he already mentioned hypothesis several times in his draft. Nonetheless, he accomplished his objective of establishing a distinct and recognizable term in the science that highlights the verified flow of biological information.

Essentially, the central dogma elucidates the fundamental mechanism by which heritable information encoded in the DNA sequence is preserved and utilized by organisms for their survival and functioning. It serves as a guiding principle for understanding the flow of genetic information within cells. DNA, RNA, and proteins, as the primary information-containing biopolymer macromolecules, play crucial roles in this process. The central dogma outlines the relationship between these molecules, with DNA serving as the repository of genetic information, RNA acting as an intermediary molecule that transcribes and transfers this information, and proteins being synthesized based on the instructions encoded in the RNA

For cells to effectively store and utilize information, they require a molecule that possesses two essential qualities. Firstly, the molecule must have the ability to duplicate itself, ensuring that a copy of the information can be faithfully passed down to daughter cells during cell division. This ensures the continuity of the genetic material across generations. Secondly, the molecule needs to be "readable" or accessible to the cellular machinery so that the information encoded within it can be interpreted and utilized for various cellular functions.

Until the 1930s, the prevailing belief among scientists was that proteins were the most likely candidates for carrying and transmitting hereditary information. This notion stemmed from the fact that proteins exhibited a wide range of functions within cells. However, it became apparent that the structure of proteins was not conducive to self-replication, which is essential for the maintenance of genetic information during cell divisions.  To fulfill this requirement, a molecule capable of serving as a replication template was necessary. By the discovery of the double helix structure of DNA, Crick proposed the idea that DNA possessed the ability to replicate itself. This molecule could generate a complementary copy of itself by utilizing the principle of base pairing. In this process, adenine (A) would pair with thymine (T), and cytosine (C) would pair with guanine (G) on the second DNA strand, effectively intertwining the two strands. This mechanism allowed for the replication of each strand, producing a mirror image molecule while preserving the original strand. The process of DNA replication follows a semi-conservative pattern, meaning that each daughter cell receives one original parental DNA strand along with a newly synthesized complementary strand. This ensures that both daughter cells inherit half of the parental DNA molecule, maintaining the genetic continuity from one generation to the next. The semiconservative nature of DNA replication is crucial for accurate transmission of genetic information and plays a fundamental role in the perpetuation of life (Figure 3.1).

Figure 3.1: Semiconservative replication.

Of course, Alternative mechanisms of replication could have been postulated, but the concept of semi-conservative replication appeared to be the most plausible explanation.  This idea was proved when a brilliant experiment conducted just one year later provided compelling evidence. Two scientists from the California Institute of Technology (Caltech), devised an ingenious approach using a heavier isotope of nitrogen atoms to make DNA. Typically, nitrogen has an atomic mass of 14 and is a fundamental component of DNA. However, a rare and heavier form of nitrogen, nitrogen-15, is also functional in the DNA molecule. Meselson and Stahl introduced nitrogen-15 into bacterial cells as a nutrient source, which the cells incorporated into their DNA during the synthesis process. As a result, the DNA molecules in these cells became significantly heavier due to the increased presence of nitrogen-15 in each DNA base and this DNA molecule can be separated from the lighter nitrogen-14 containing DNA.

Following their incorporation of nitrogen-15 into the DNA of bacterial cells, Meselson and Stahl sought to determine whether the semi-conservative model of DNA replication held true. They achieved this by transferring the bacterial cells to a growth medium containing only nitrogen-14, effectively depriving them of nitrogen-15. If the semi-conservative model was correct, the DNA would exhibit a distinct pattern of halving its size with each round of cell division. In the first round of cell division, each strand of DNA molecule consisting of nitrogen-15 would pair with newly synthesized copy composed of nitrogen-14. Subsequently, in the next round of cell division, the original DNA molecules containing nitrogen-15 would be diluted by exactly half again and so on, resulting in a reduction in size. As anticipated, the experimental results aligned perfectly with the predictions of the semi-conservative model, with the DNA molecule halving in size of the initial nitrogen-15 DNA in each round of cell division, while the content of nitrogen-14 in the DNA molecule doubling by each cell division. The observed pattern of DNA replication unequivocally demonstrated that cells employ a semi-conservative mechanism to faithfully copy and transfer the hereditary information encoded in DNA to subsequent generations. 

DNA replication is a very complex phenomenon happing in every cell once they are destined to divide. The entire DNA content of cell is copied in the semiconservative manner providing survival information for the next generation. A somatic cell (not a germline: ie., sperm or ovum) in our body contains 6.4 billion base pairs of DNA molecule. Almost all of these base pairs are copied and the new mirror copy entangles back with the parental strand into a double helix form. The replication process is energetically demanding, as the DNA molecule's natural state is a tightly wound double helix. Unwinding the DNA strands requires a lot of energy.

DNA replication involves a multitude of proteins that play critical roles in various steps of the process. To initiate replication, the tightly wound DNA molecule needs to be relaxed and unwound, allowing access to the individual strands. This task is accomplished by topoisomerase enzymes. Topoisomerases are responsible for relieving the tension and torsional stress of the DNA molecule. Following the relaxation of the DNA, the helicase enzyme comes into action. Helicases are ATP-dependent motor proteins that bind to the DNA molecule and move along the strands, separating them from each other by breaking the hydrogen bonds between complementary nucleotides (between A and Ts and C and Gs). By harnessing the energy from ATP hydrolysis, helicases unwind the double helix, creating the replication fork where new strands can be synthesized.

Many other enzymes help helicases in this process. It would take about 4 years for our whole DNA content to be replicated if it was to happen from one end to another. Instead, due to the presence of multiple origins of replication in our genome, DNA replication is highly efficient and rapid. This is where helicases bind to DNA and start unwinding. By having numerous origins of replication distributed throughout the genome, DNA replication can occur simultaneously at multiple sites. This simultaneous initiation of replication at multiple origins allows for the rapid duplication of the entire genome within approximately an hour.

As the helicase and other enzymes move through DNA, opening it up, they leave two single strands hanging separately from each other. Other proteins prevent these free strands from re-binding replication is completed. DNA polymerase comes into play when the single strands are free. As the name suggests, DNA polymerase is an enzyme that catalyzes the polymerization of DNA molecules using another DNA strand as a template. DNA polymerase moves along the single-stranded DNA and pairs new nucleotides with those in the template. This is where the fundamental pairing rule of A with T and C with G comes into play. Because the three-dimensional chemical structure of DNA polymerase allows for the insertion of a C nucleotide when it encounters a G in the template, and vice versa, as well as the matching of A with T (Figure 3.2).

Figure 3.2: Simple schematic of DNA replication in a semiconserved fashion

Now each single-stranded DNA molecule is doubling up with the newly synthesized strand by the remarkable action of DNA polymerase. This enzyme not only undertakes the critical task of replicating DNA but also meticulously proofreads its own work, ensuring the utmost accuracy in the replication process. The significance of this proofreading capability cannot be overstated, as even the slightest error in base pairing can have profound consequences. In fact, within just two rounds of replication, an erroneous insertion of a C instead of an A in front of a T can set off a chain reaction. In subsequent rounds of replication, that misplaced C would serve as the template, inevitably leading to its pairing with a G. As a result, the original A-T base pair is transformed into a C-G base pair, which in turn alters the codon sequence for protein synthesis. Such unexpected changes in the DNA sequence have been linked to the development of severe diseases, including cancer. Therefore, the proofreading ability of DNA polymerase stands as a formidable safeguard, diligently upholding the fidelity of the genetic code.  Moreover, in addition to its critical proofreading function, DNA polymerase boasts an impressive attribute known as high processivity. This characteristic signifies its remarkable capacity to swiftly and efficiently pair a vast number of bases per second as it deftly traverses along the DNA template strand. Some polymerase could pair up to 1000 bases per second while rapidly moving through the DNA template strand. The combination of proofreading prowess and exceptional processivity empowers DNA polymerase to play a vital role in the accurate replication of the DNA molecule, thereby preserving the integrity of genetic information for generations to come.

The revolutionary technique of Polymerase Chain Reaction (PCR), harnessing the remarkable power of DNA polymerase, has forever transformed the landscape of molecular biology. In recognition of his groundbreaking contribution, Kary Mullis was awarded the Nobel Prize in Chemistry in 1993. PCR allows for the exponential amplification of a specific gene or DNA segment within a test tube, even amidst a vast sea of other genetic material. With a simple set of chemicals, including free nucleotides and DNA polymerase enzyme typically derived from bacteria, this technique enables the targeted multiplication of a single gene in a sample, reaching astonishing levels of amplification exceeding 1,000,000,000,000-fold after just 40 repeated cycles (Figure 3.3). The process, which can now be completed in less than two hours, has found widespread application across numerous fields, revolutionizing areas such as medical diagnostics, genetic research, forensic analysis, and more.

Figure 3.3: PCR reaction

PCR has sparked the development of numerous derivative methods, each serving a unique and crucial purpose in various applications. One such variation involves amplifying RNA instead of DNA, opening up new avenues of investigation. Among the earliest and most impactful applications of PCR was its use in paternity testing. By amplifying a specific gene sequence from samples obtained from individuals in question, PCR provided a means for DNA fingerprinting and the determination of shared gene sequences. This technique has found widespread use in medical diagnostics, offering valuable insights into conditions such as cancers and anemic diseases. In the field of organ transplantation, PCR plays a vital role in tissue typing, ensuring compatibility between donors and recipients. When it comes to diagnosing specific types of infectious diseases, whether bacterial or viral, PCR stands as the gold standard, providing unparalleled accuracy and sensitivity. In forensic science, PCR has revolutionized investigations by enabling the analysis of DNA samples collected from crime scenes. Furthermore, ancient and evolutionary studies have greatly benefited from the wide application of PCR, allowing researchers to unlock secrets buried in the genetic material of long-extinct species. Today, PCR has become an indispensable and routine method employed in the vast majority of biological research laboratories, underscoring its immense importance and impact on scientific advancements.

DNA was able to perfectly meet the first criteria of duplication for hereditary purpose by the replication process. However, the second criteria of “readability” for cells was more complicated as there were more steps involved in this process. It was known that proteins are the most functional units in the cells, and DNA serves as the hereditary unit, but what does the RNA do in cells and where it comes from?

The proposal of the central dogma by Crick brought about a significant surge of research in the field of RNA in the 1950s and 60s, leading to key discoveries regarding its nature and function within cells. According to the central dogma, RNA is synthesized from DNA, which serves as a template for its production. In a process which is called Transcription, cells produce RNA from DNA. Transcription shares certain similarities with DNA replication. In both processes, DNA must be unwound to allow the protein machinery responsible for RNA synthesis (rather than DNA synthesis in replication) to access it as a template.  The key player in both cases is a polymerase enzyme, but in transcription, it is specifically referred to as RNA polymerase rather than DNA polymerase. The fundamental distinction lies in the building blocks utilized by the polymerase enzymes. DNA polymerase employs deoxynucleic acids, while RNA polymerase utilizes ribonucleic acids. The distinction between these two types of molecules is merely an oxygen atom, yet the enzymes demonstrate remarkable efficiency in accurately incorporating the appropriate molecule into the growing polymer.

RNA polymerase follows the same base pairing logic as DNA polymerase, with a slight variation. While DNA polymerase pairs cytosine (C) with guanine (G) and adenine (A) with thymine (T), RNA polymerase pairs cytosine (C) with guanine (G) as well. However, in RNA molecules, thymine (T) is replaced by uracil (U). Therefore, during transcription, RNA polymerase pairs uracil (U) with adenine (A). The end result of the transcription process is the production of a single-stranded RNA molecule that separates from the DNA template. The DNA strands then reassociate with their respective sister strands, reforming the double helix structure (Figure 3.4).

Figure 3.4: DNA transcription

There are specific regions in DNA known as promoters, which are located at the beginning of genes. These promoter sequences are recognized by some accessory protein factors that summon the RNA polymerase to the site, initiating the transcription process. Then you have some specific sequences at the end of genes which helps in release of RNA polymerase from DNA. Similarly, there are specific sequences at the end of genes that aid in the release of RNA polymerase from DNA. These markers, along with other regulatory factors, enable cells to precisely initiate transcription of a single gene at the right place and ensure its completion where it has to be finished. Tens to hundreds of RNA polymerases might come one after another on the same gene and transcribe it many times to generate multiple copies of the RNA molecule. This depends on the cellular demand for that specific RNA. When the cells are done, all the RNA polymerases are released and the DNA gets closed to its double helix structure. However, the question remains: how do cells determine which genes should be transcribed???!!!

All of the cells in your body contain the identical genetic information encoded within their DNA. However, despite this uniformity, each cell type possesses distinct characteristics and functions. Cardiac cells rhythmically contract to facilitate the beating of your heart, while neuronal cells in your brain enable complex cognitive processes and have a totally different morphology. Similarly, bone cells contribute to the structural framework of your skeleton, and white blood cells kill microbial invaders. The DNA of every cell already carries the complete blueprint required to generate all the different cell types present in your body. However, the manifestation of these diverse cellular functions arises from the differential activation of genes through the process of transcription in each particular cell.

There are certain genes, known as housekeeping genes, that need to be transcribed in all cells regardless of their specialized functions. Housekeeping genes are involved in essential cellular processes such as metabolism and basic cellular maintenance. They provide the necessary foundation for cell survival and function. While these genes are universally active, each cell type (e.g., cardiac and neuron cells) also possesses its own distinct set of genes that are specifically tailored to fulfill its unique role. These set of genes are known as cell type-specific genes. These genes are responsible for conferring the specialized characteristics and functions of specific cell types. For example, cardiac cells express genes that are vital for their contractile function and rhythmic beating, while neuronal cells express genes that contribute to the signaling network of connections within the brain. By selectively transcribing these cell type-specific genes, cells acquire the necessary tools and machinery to carry out their specific tasks. In each type of cells, their cell type-specific genes are transcribed while other genes are silent or shut down. The regulation of gene transcription is a tightly controlled process, orchestrated by a complex interplay of protein factors within the cell. These factors act as regulators, ensuring that the appropriate genes are transcribed in specific cell types while others are silenced.

The transcribed RNA from genes in the central dogma, specifically messenger RNA (mRNA), serves as the template for protein synthesis. However, there are several other types of RNA in cells, performing various functions vital for cellular processes. Messenger RNA (mRNA) is responsible for carrying the genetic instructions from DNA to the protein synthesis machinery. It acts as an intermediary or "messenger" between DNA and protein. The mRNA molecules then interact with specialized protein complexes called ribosomes. The ribosome "reads" the mRNA molecule in a sequential manner, following the instructions encoded in the mRNA's nucleotide sequence. They use amino acids as the building block for protein synthesis using mRNA as template.

Ribosomes, the cellular machinery responsible for protein synthesis, are complex macromolecules composed of both proteins and RNAs.  This composite molecule has more RNA than protein and these ribosomal RNAs are called rRNA. rRNA is a functional type of RNA that is not intended to serve as a template for protein synthesis, unlike mRNA. Despite its non-coding role, rRNA is the most abundant type of RNA found in cells. Its primary function is to guide the mRNA molecule into the appropriate position within the ribosome and assist in the proper folding of ribosomal proteins, ensuring the formation of the correct three-dimensional structure necessary for accommodating mRNAs during translation (Figure 3.5).

Figure 3.5: mRNA translation in ribosomes for protein synthesis

The structure and sequence of rRNAs exhibit remarkable conservation across diverse species, ranging from bacteria to humans. Their crucial role allows minimal variation in their sequence among species, and any significant variation in their sequence resulting in non-functional ribosome would be lethal to the organism. In fact, the conservation is so pronounced that rRNA sequences are employed in taxonomic and phylogenetic studies to classify and establish relationships among different species. While there are slight variations in the size of ribosomes between eukaryotes and prokaryotes, the overall architecture and functional components remain largely similar within each domain.  The vital role of ribosomes in survival, coupled with its minimal difference between eukaryotes and prokaryotes, has enabled us to leverage these factors in the development of antibiotics. Different regions of ribosomes are exploited to design chemicals that would inhibit protein synthesis in prokaryotes while sparing the eukaryotic cells’ ribosomes. Antibiotics such as Neomycin, Tetracycline, Chloramphenicol, Geneticin, and Puromycin are examples of compounds that disrupt various stages of ribosomal protein synthesis in prokaryotes. These drugs exploit the differences between bacterial and eukaryotic ribosomes, allowing them to specifically target bacterial cells while having no effect on our own cells.  

Ribosomes were first discovered in the 1950s and the significant contribution and impact of this discovery were recognized by the Nobel Prize in Physiology or Medicine which was awarded in 1974 to Albert Claude, Christian de Duve, and George E. Palade, for their groundbreaking work on the structural and functional analysis of cells, including the discovery of ribosomes. However, the story of ribosomes did not end there. In the following decades, extensive research focused on unraveling the detailed structure and understanding the mechanism of function in ribosomes. Given its importance in all biological organisms, this pursuit of knowledge culminated in another Nobel Prize, this time in Chemistry, awarded in 2009 to Venkatraman Ramakrishnan, Thomas A. Steitz, and Ada E. Yonath. Ada E. Yonath (Figure 3.6) was the first middle eastern and first Israeli women to win a Nobel prize in science.

                             Figure 3.6: Ada E. Yonath

After mRNA is positioned within the ribosome, the process of protein synthesis commences. Amino acids are sequentially delivered to one of the two entry sites of the ribosome, aligning with the mRNA sequence to synthesize the corresponding protein. The ribosome consists of two distinct entry sites and one exit site for amino acids. The first entry site accommodates the incoming amino acid, while the second entry site receives the subsequent amino acid in the sequence. Upon the arrival of the lagging amino acid at the second entry site, the ribosome catalyzes the formation of a peptide bond between the proceeding amino acid and the lagging amino acid, resulting in the creation of a growing polypeptide chain. The proceeding amino acid is released from its carrier molecule and remains bonded to the lagging amino acid, forming a chain of amino acids. Subsequently, the carrier molecule carrying the proceeding amino acid moves forward to the exit site, leaving the first entry site unoccupied. Meanwhile, the lagging amino acid, now bonded to the growing polypeptide chain, moves into the first entry site, where it assumes its designated position. Simultaneously, the ribosome advances along the mRNA, allowing the second entry site to align with the next codon on the mRNA strand, thereby preparing for the next round of protein synthesis. This process of amino acid delivery, peptide bond formation, and ribosome movement continues iteratively along the mRNA strand until the entire protein is synthesized (Figure 3.7). 

Figure 3.7: Polypeptide chain formation by ribosome and mRNA

A crucial player in the process of protein synthesis is a specialized RNA molecule known as transfer RNA (tRNA). It serves as the carrier molecule that transports amino acids to the ribosomes for incorporation into the growing polypeptide chain (Figure 3.7). tRNAs are relatively short RNA sequences, typically around 80 bases in length, and possess a unique structure resulting from the partial complementarity of different regions within the same molecule. This structural arrangement gives rise to a distinctive cloverleaf shape when visualized in two dimensions, while in three dimensions, tRNAs adopt an L-shaped structure. At one end of the L-shaped tRNA molecule, a specific amino acid is conjugated or attached. Each of the 20 different amino acids found in proteins is tagged to the corresponding tRNA determined by the specific sequence of that tRNA. On the other end of the tRNA molecule, there is a three-base sequence known as the anticodon. The anticodon on tRNA is unique for each amino acid, and it is complementary to a specific three-base codon found on the mRNA strand. The pairing of the anticodon on tRNA with its complementary codon on mRNA allows for the stable insertion of the tRNA carrying the appropriate amino acid into the entry site of the ribosome. This process, in which the nucleotide code present in DNA and mRNA is translated into the amino acid code that makes up proteins, is aptly named translation. Through the coordinated action of tRNA molecules, mRNA templates, and ribosomes, the information encoded in the sequence of nucleotides is deciphered and utilized to synthesize polypeptide chains, ultimately giving rise to functional proteins with specific structures and functions.

This is how the central dogma of biology from DNA to RNA and then proteins works through replication, transcription and translation. While keeping the inheritance information of DNA through replication in each generation of cell division, cells transcribe that information to RNA, and order the synthesis of cell’s functional units (i.e., proteins) by translation.

The tremendous and continuous efforts of scientists spanning across decades have played a pivotal role in unraveling of the "mystery of life" triangle. Although these are the basic processes happening in each cell, we are still trying to decipher the inherent details of each step. Even in the present day, a substantial portion of biological research is dedicated to unraveling the intricate mechanisms underlying these processes within various contexts of health and disease. Although we know a lot about their mechanistic details, yet all three steps are vastly fine-tuned at the molecular level to meet the demand of our cells, differently regulated by many complex ways in each specific cell. Their malfunction leads to debilitating diseases, and as such we try to understand these processes in many pathological contexts such as cancer.

The Human Genome

As discussed in the preceding chapter, genes serve as the masterminds of biology and life. They hold the power to shape our inherent characteristics, influence our physical form, and ultimately determine our destiny at both the cellular and organismal levels. Collectively, the entirety of an organism's or individual's genes is referred to as the genome. To be more precise, the genome encompasses all the DNA content within an individual. The distinction is that not all of this DNA is solely composed of genes. In fact, the genome comprises numerous functional units within its DNA content that do not undergo transcription, yet remain vital for the proper functioning and maintenance of our genetic blueprint.

The bacterial genome comprises all the DNA content obtained from bacterial cells, encompassing the genetic material necessary for their functioning. Similarly, the human genome refers to all the DNA content obtained from human cells. However, our cells have two sources of DNA. The first and primary source is the DNA within the nucleus of our cells, which contains the vast majority of our genetic information. The second source is the DNA found within mitochondria; the cellular organelle known as cell’s powerhouse. While mitochondria do possess a small number of genes essential for their own function, these genes are often studied separately from the nuclear genome. When referring to the human genome, the primary focus is on the nuclear genome, which harbors the majority of our genetic material.

The human genome consists of approximately 2 times 3.2 billion (3,200,000,000) base pairs, which represents a doubling of the 3.2 billion base pairs contributed by each parent. These base pairs are organized into 23 large DNA molecules known as chromosomes. Each chromosome is a single DNA molecule that is tightly coiled and wrapped upon itself (Figure 4.1). In somatic cells (all cells except sperm and egg), humans have a pair of these 23 chromosomes, resulting in a total of 46 chromosomes. Half of the chromosomes are inherited from the mother, while the other half are inherited from the father. Therefore, each cell in the human body contains a total of 6.4 billion base pairs, with each chromosome pair contributing 3.2 billion base pairs.

Figure 4.1: structural entanglement of a chromosome. 

Germ cells, specifically egg and sperm cells, are an exception to this pattern. Germ cells are haploid, meaning they contain only one set of each chromosome. Therefore, egg and sperm cells each contain the 3.2 billion base pairs of the human genome. When fertilization occurs and a sperm fuses with an egg, the resulting zygote (the fused cell) becomes diploid, having two copies of each chromosome - one set from the mother and one set from the father. This diploid state restores the total of 6.4 billion base pairs in the zygote. 

If we were to linearly spread out the genome of a single human cell, it would extend to approximately 2 meters in length. This is an astounding fact considering that the average size of a human cell is only about one-tenth of a millimeter. To put it into perspective, this means that if we were to divide a meter into 10,000 parts, the length of an average human cell would be equivalent to one of these divisions. Furthermore, the nucleus of a cell, which houses the majority of the DNA, has an average diameter of around 10 micrometers. To visualize the challenge of fitting a 2-meter-long DNA molecule into such a small space, imagine cramming that length into a space equivalent to one of these divisions, which would be 100,000 times smaller.

To accomplish this feat, our cells utilize an incredible level of packaging through a highly efficient process. Our cells achieve this level of packaging by the help of proteins. There are specific proteins responsible for folding the DNA and other proteins around which the DNA is wrapped. These proteins help to condense and compact the DNA molecule, allowing it to fit within the confined space of the nucleus.

One of the key proteins involved in the packaging of DNA is called histones (Figure 4.1). Histones are small, ball-shaped proteins around which DNA molecules take approximately two turns. Within the nucleus, there are numerous histone proteins, and the DNA wraps around them and stacks on top of each other, forming a highly organized structure. Other larger proteins act as scaffolds, assisting in maintaining the tight packaging of DNA, enabling it to fit within the limited space of the nucleus.

Histones are the major players in gene transcription. They act as receivers of small chemical modifications acting as molecular cues, such as acetylation and methylation modifications. These modifications can cause the DNA to unwind from the histones, making it accessible for the assembly of RNA polymerases, to transcribe the open genes. Once the transcription process is complete, the molecular cues are typically removed, and the DNA rewraps around the histones, returning to its compact and silent form. Interestingly, histones are one of the most conserved proteins in all eukaryotic organisms. They exhibit remarkable similarity across different species, from fungi and algae to plants and humans.  Even in prokaryotes and bacteria, there are histone-like precursor proteins present. This highlights the significance of histones in DNA packaging across diverse forms of life. Regardless of the species, the need to efficiently package DNA within a limited space has led to the evolutionary conservation of histones and their vital role in genome organization.

After the DNA wraps around histones and forms a compact structure, we encounter a unique repetitive DNA sequence known as the centromere (Figure 4.2). The centromere is a specialized region of DNA that plays a critical role in chromosome segregation during cell division. It acts as an attachment site for a complex of multiprotein Centromeres are the cross point of each chromosomes. Centromeres serve as the meeting point or cross point of each chromosome. Chromosomes, particularly during cell division, often adopt an X-shaped structure, with the centromere being the point where the two arms of the X intersect. It is important to note that not all chromosomes are symmetrical in their proportions. Some chromosomes have one arm longer than the other, resulting in the centromere not being positioned at the exact middle of the chromosome.

Figure 4.2: Chromosome with centromere structure

The naming of X Chromosome is not directly related to their shapes. The X chromosome was initially referred to as the X element when it was first discovered, as scientists were uncertain about its nature and function. However, as further research progressed, it was recognized as a distinct chromosome and subsequently named the X chromosome. after its sequential order in the alphabetic system of chromosome classification. It was discovered after the X chromosome, and by chance, its structure appears somewhat Y-shaped. The Y chromosome consists of two very short arms that appear fused together, resembling the shape of the letter "Y."

But how the end of each chromosome is organized?

If the ends of chromosomes were left exposed as free DNA, they would be susceptible to random fusion with neighboring chromosomes or degradation. However, nature has provided a solution to this potential problem by implementing a protective mechanism involving highly conserved repetitive DNA sequences known as telomeres. Telomeres consist of repeated short sequences of DNA that serve as protective caps at the ends of chromosomes. These telomeric sequences are bound and safeguarded by a specialized protein complex called shelterin.

The specific number of repetitive sequences in telomeres can vary between different species. For instance, in vertebrate animals, including humans, the telomeric sequence is commonly TTAGGG. These repetitive sequences are present thousands of times at the ends of each chromosome, forming a unique and distinctive pattern. This repetition of telomeric DNA is crucial for maintaining the integrity and stability of the chromosome ends. One fascinating aspect of telomeres is that their length is one of the factors that determines our longevity.

A small portion of chromosomes’ ends is lost during each DNA replication in cell division. These end parts are very difficult to replicate, resulting in the new daughter cells receiving a slightly shorter version of the parental chromosome. One of the main functions of telomeres is to protect the loss of important genes during this replication error. Instead, it is the repeated short sequence of telomeres that gets lost. Therefore, the rate of telomere shortening is directly related to the number of times your cells undergo replication. As we age, more cell divisions and replications occur, leading to the gradual erosion of telomeres. When telomeres reach a critical length, cells enter a state of permanent growth arrest known as senescence. This process occurs as a protective mechanism to prevent potential damage to the organism caused by the loss of genes. If cells were to continue dividing with critically short telomeres, it could increase the risk of developing cancer in many cases. Senescence acts as a safeguard against uncontrolled cell growth and the potential harmful consequences associated with it.

In the early 1960s, Leonard Hayflick made a significant discovery that cells cultured in petri dishes have a limited capacity to divide before entering a non-replicative state. He observed that after approximately 50 rounds of cell division, cells cease to divide while remaining viable; senescence. This phenomenon, now known as the Hayflick limit, highlighted the finite replicative potential of cells. As we age, we accumulate more senescent cells, further emphasizing the correlation between telomere length, replication effects, and the onset of senescence. Scientist have recently shown that if we clear senescent cells from mouse, we can extend their lifespan!

Cells possess a unique enzyme called Telomerase, which can repair and add telomeres to the end of chromosomes. Telomerase has the remarkable ability to counteract the replication-associated loss of chromosome ends. However, in most of our somatic cells (non-reproductive cells), telomerase is not actively expressed. As a result, these cells experience the consequences of repeated replication, leading to telomere shortening over time. Interestingly, telomerase is expressed in specific cell types, including stem cells, gametes (sperm and egg cells), and cancer cells. Stem cells are essential for the development and maintenance of tissues in our bodies in scenarios such as repeated wound healing. They have the remarkable capability to self-renew and differentiate into various cell types. Given their extensive replicative potential, stem cells require the continuous expression of telomerase to prevent telomere shortening and maintain their proliferative capacity. Our gametes, especially sperm cells, undergo constant production to ensure the perpetuation of our species. Therefore, it is crucial for these cells to maintain the expression of telomerase. However, most of our somatic cells do not need telomerase, except some immune cells at low level. This selective expression of telomerase in specific cell types contributes to the limitations of our longevity. Now, you may wonder why telomerase is not expressed in all our cells to potentially extend our lifespan. Because nature does not care about your concerns for living longer life! The reason simply lies in the fundamental principles of nature. Nature's primary concern is the survival and propagation of our species. As long as an individual lives long enough to reproduce and adequately care for their offspring until they reach maturity, nature's goal is fulfilled. Stem cells and gametes play crucial roles in this reproductive process and are therefore endowed with telomerase expression to ensure their continued functionality. Individuals who do not express telomerase in these critical cells would not survive or be able to reproduce, thus their genetic contribution to the species would be eliminated. On the other hand, the loss of telomerase expression in other somatic cells does not significantly impact our overall fitness, as these cells are not directly involved in reproduction or the nurturing of offspring. In fact, the expression of telomerase in somatic cells can pose a significant risk, as it provides a potential advantage for the formation of cancer cells. While the absence of telomerase expression in most somatic cells may limit our lifespan, it aligns with the broader objectives of nature, which prioritize the continuity and survival of our species rather than individual longevity. The delicate balance between telomerase expression and regulation in different cell types is a fascinating area of study.

The discovery of telomeres and telomerase initially sparked great hope for increasing human longevity. People envisioned the possibility of extending our lifespan by manipulating somatic cells to express telomerase. However, these hopes were shattered when scientists discovered that cancer cells re-activate telomerase expression. Cancer cells undergo repeated and uncontrolled cell divisions constantly, effectively becoming immortal in their capacity to divide. Unlike normal cells, they do not experience the Hayflick limit or enter senescence. This unrestricted growth is what enables tumor formation. It was observed that over 90% of all cancers re-express telomerase, highlighting the dependence of most cancer cells on the maintenance of their telomeres. This realization led us to understand that reactivating telomerase to increase lifespan is a dangerous approach due to its association with cancer development. However, this newfound knowledge opened up new possibilities in the fight against cancer. Researchers began exploring the potential of inhibiting telomerase activity as a therapeutic strategy to target cancer cells. Inhibiting telomerase could disrupt the telomere maintenance process in cancer cells, eventually leading to their growth arrest or even death. This avenue of research has become an active and promising field in the pursuit of novel cancer treatments. The significance of the discoveries surrounding telomeres and telomerase was recognized with the awarding of the Nobel Prize in Physiology or Medicine in 2009 to Elizabeth H. Blackburn, Carol W. Greider (Figure 4.3) and Jack W. Szostak.

Figure 4.3: Right: Elizabeth H. Blackburn; Left:  Carol W. Greider

Another major repetitive sequence in our genome is Transposons or Transposable Elements. Barbara McClintock (Figure 4.4) made a ground breaking discovery in the field of genetics with her work on transposons. While studying maize which almost 90% of its genome is made of transposable elements, she noticed the occurrence of different colors within the same breed. Intrigued by this observation, she delved into the genetic basis of these variations.

Figure 4.4: Barbara McClintock

Through her meticulous analysis, McClintock found that certain segments of chromosomes were capable of changing their positions within the genome. These mobile DNA sequences, which she termed transposons, played a significant role in generating genetic diversity and influencing gene expression in maize. McClintock's seminal research on transposons in maize was published in 1953.

However, her findings were initially met with skepticism and were largely neglected by the scientific community for many years. It was only in the 1980s, with the rediscovery of transposons in bacteria and further research on these genetic elements, that McClintock's work gained the recognition it deserved.

In 1983, Barbara McClintock was awarded the Nobel Prize in Physiology or Medicine for her discoveries regarding transposable elements. This honor made her the first woman to win an unshared Nobel Prize in the field of medicine. Her remarkable contributions to the understanding of genetic mechanisms, particularly the role of transposons, have had a profound impact on our knowledge of genome structure and evolution. McClintock's perseverance and ground breaking research have cemented her status as a pioneering figure in the field of genetics.

Transposons, often referred to as jumping genes, are short DNA sequences that have the remarkable ability to move within our genome. They can excise themselves from their original location and insert themselves randomly into other regions of the genome. Some transposons even undergo duplication, creating multiple copies that are inserted randomly throughout the genome. These sequences, despite their abundance, still pose a mystery when it comes to their precise function.

Oddly, comprising approximately 50% of our entire genome, transposons are pervasive and yet their role remains largely unclear. They appear to be selfish elements, driven by their own desire for propagation and control. However, their random insertions can have significant implications for our health. When a transposon inserts itself into a functional gene, it can disrupt its normal function and potentially lead to mutations that contribute to the development of diseases such as cancer. Hemophilia, another well-known disorder that is characterized by impaired blood clotting, is among the conditions that may be linked to the activity of transposons. While cells employ various mechanisms to minimize and suppress the function of transposons, these elements still make up a substantial portion of our genome.

Some types of these jumping genes have originated from viruses and have left their mark in our DNA. Surprisingly, viruses like HIV exhibit similar behavior to transposons and produce comparable proteins, hinting at a possible shared ancestry. This intriguing connection raises the question of why we still harbor these elements in our genome.

Scientific evidence suggests that transposable elements play significant roles in evolution. They are found in almost every organism on the planet, indicating their widespread presence and potential importance. The random insertion of these elements can have diverse effects, and in certain cases, it can even lead to advantageous outcomes, conferring evolutionary benefits. While transposons may be considered as remnants of ancient viral infections, their impact on our genome extends beyond their origins. They have become integral components that shape our genetic landscape and contribute to the dynamic nature of evolution.

The Y chromosome, known for its abundance of transposons, is considered the fastest-evolving chromosome. However, it's important to note that this doesn't imply that males are evolving at a faster rate than females. Evolution occurs at the species level, encompassing both sexes. Y The Y chromosome plays a crucial role as a sex-determinant chromosome, determining the sexual characteristics of an organism. Its presence or absence determines whether an individual develops as male or female. In the presence of a Y chromosome, an individual develops as male, while its absence results in a female phenotype. On the other hand, the X chromosome is present in both sexes. Females have two X chromosomes, while males have one X and one Y chromosome. Hence, males are typically identified by the XY chromosome combination, while females possess the XX chromosome configuration. It's worth mentioning that there are instances of genetic abnormalities, such as XXY or XYY chromosomes, which deviate from the typical male and female chromosomal patterns.

With all the sex and gender identity debates going on at this period, it is important to acknowledge that the classification of sex in this context refers to the classical biological categorization based on the presence of X and Y chromosomes that typically determine male and female phenotypes. While the X and Y chromosomes play a significant role in determining biological sex in the vast majority of the human population, it is worth noting that there can be additional factors that contribute to an individual's sexual phenotype or gender identity. Epigenetic modifications and hormonal balances during embryonic development can sometimes have an impact on sexual development and may occur independently of the presence of X and Y chromosomes. However, it is crucial to emphasize that such occurrences are relatively rare and do not negate the general understanding of biological sex based on chromosomal patterns.

Human males produce two types of sperm, carrying either an X or Y chromosome, while females produce eggs that contain an X chromosome. In addition to the sex chromosomes, sperm and egg carry 22 autosomal (non-sex) chromosomes. The combination of sperm and egg determines the sex of the resulting child. If a sperm carrying an X chromosome fertilizes the egg, the child will have XX chromosomes and develop as female. If a sperm carrying a Y chromosome fertilizes the egg, the child will have XY chromosomes and develop as male. Human males produce two types of sperms, each with either of X or Y chromosomes, plus 22 autosome (non-sex) chromosomes. Human females produce only one type of egg which has X chromosome from either of the XX chromosomes, plus 22 autosome chromosomes. Thus, it is biologically the contribution of the father's sperm that ultimately determines the sex of the child. despite the old misconceptions that women have control over determining the sex of a child! Human ignorance has put huge burden on women for child bearing with intention of having a baby with a specific sex (mostly male) through history, while this is men who are responsible for sex determination, though even this is uncontrollably!

Most genes in our genome exist in two copies, one inherited from the mother and the other from the father. These genes are usually expressed from both copies. However, the Y chromosome is an exception to this pattern. As mentioned, the Y chromosome lacks a maternal counterpart, and therefore its genes are unique to males. Interestingly, the Y chromosome contains the fewest number of protein-coding genes among all the chromosomes in the genome. Over the course of evolution, the Y chromosome has undergone a process called degeneration, which involves the loss or transfer of genes to other chromosomes. This has resulted in the Y chromosome becoming smaller in size compared to other chromosomes. However, the genes on the Y chromosome do not simply disappear; they often get transferred to other chromosomes in the genome.

In contrast, the X chromosome carries a significant number of protein-coding genes. Many of these genes are not directly involved in sex determination, unlike the Y chromosome. Y chromosome codes for a protein that is called Testis-determining factor (TDF), which as the name suggests, it is responsible for the development of testes.

A very fascinating phenomenon that happens in females is X-inactivation. Males have only one X chromosome and accordingly one copy of the genes in the X chromosome. This is unlike the other 22 pair of autosomal chromosomes which provides 2 copies for each gene (one from mother, one from father). In contrast, females have two X chromosomes and two copies of its genes. Females shut down one of their X chromosomes in order to compensate for the dosage of genes that male can express only from their single X chromosome. Every cell in the body of a female has two X chromosomes, but one of them is inactivated and they have similar expression level of the genes in the X chromosome as the male cells. This process of X-inactivation occurs early during embryonic development. At a specific stage, one of the X chromosomes in each cell is chosen for inactivation. The choice is random and independent in each cell, resulting in a mosaic pattern of X chromosome activity throughout the female's body.

Once an X chromosome is inactivated, it remains inactive throughout the lifetime of the cell and its descendants. The inactivated X chromosome becomes highly condensed and forms a structure called a Barr body. This ensures that the same X chromosome remains inactivated in all daughter cells derived from the initial embryonic cell.

The random X-inactivation leads to a diverse pattern of gene expression in different cells of a female's body. Some cells will express genes from the paternal X chromosome, while others will express genes from the maternal X chromosome. This mosaic pattern is responsible for the variability observed in female traits related to X-linked genes.

The classic example of this is the fur color of cats which is a great illustration of X-inactivation. Since the genes responsible for the fur color are located on the X chromosome, the inactivation of either the maternal or paternal X chromosome in different cells results in patches of fur with different colors in female cats (Figure 4.5).

Figure 4.5: Two female cats showing different fur color pattern due to random X-inactivation.

X-inactivation is an irreversible process that occurs in all somatic cells of females. However, since female egg cells possess only one X chromosome, a reactivation mechanism is necessary. During cell division, female gametes initiate the reactivation of the previously silent X chromosome. As a result, the two resulting egg cells will each receive one of the active X chromosomes.

The X chromosome that is destined for inactivation initiates the expression of several long non-coding RNAs. These RNAs bind to their corresponding X chromosome and recruit specific proteins. These proteins then modify the DNA and histones by adding chemical molecules such as methyl groups. These modifications serve as signals for the shutdown and compaction of the chromosome, preventing gene transcription. Importantly, these chemical modifications can be maintained on the gene or histone structure and can be inherited by the next generation of daughter cells. Thus, they act as a form of hereditary information, even though they are not part of the DNA sequence itself. These molecular signals and modifications are collectively called Epigenetics since they are out of the genetic information yet they are involved in hereditary transmission of gene expression patterns.

Epigenetics encompasses mechanisms that can modify the pattern of gene expression, allowing for the transmission of these expression patterns to the next generation as a form of inheritance. In most cases, the next generation refers to daughter cells, such as when dividing gut cells pass on their epigenetic signatures to their offspring. However, there are also instances of epigenetic inheritance in organisms through various mechanisms. The caveat is that epigenetic patterns are highly influenced by environmental factors, and these changes can be transmitted to your child even if your genetic traits do not predispose you to a particular characteristic. A compelling example of this phenomenon is seen in type-2 diabetes. Even if you do not have a genetic predisposition to diabetes, adopting an unhealthy lifestyle can lead to epigenetic changes that increase the risk of diabetes in your offspring. Studies conducted on mice have demonstrated that feeding them a high-fat diet, which induces diabetes, can trigger epigenetic modifications in their sperm. These modifications can then enhance the likelihood of diabetes in their offspring. These kind of findings emphasize the significant impact of environmental factors on gene regulation and the potential for epigenetic changes to influence the health and traits of future generations.

One of the most fascinating demonstrations of the profound impact of epigenetics is observed in identical or monozygotic twins. These twins possess an identical genomic sequence (with the exception of potential random mutations in each individual), yet they exhibit variations in their epigenomes. Although they share many similarities, they also display distinct features such as differing heights, facial characteristics, levels of intelligence, and even unique attitudes. These variations can be attributed to differences in epigenetic patterns, which result in diverse patterns of gene expression. Epigenetic patterns in identical twins typically accumulate and diverge after birth, influenced by various environmental exposures such as nutrition, stress levels, and illnesses. As a result, we often observe greater dissimilarities between identical twins as they grow older compared to when they are younger. This phenomenon provides compelling evidence that while our genetic makeup lays the foundation for our traits, the dynamic interplay between genes and the environment, as mediated by epigenetic mechanisms, plays a crucial role in shaping our individual characteristics.

Epigenetics indeed plays a significant role in the transmission of environmental-induced psychological problems, including conditions such as PTSD, depression, and anxiety. These disorders can be inherited by subsequent generations through epigenetic modifications. An intriguing study conducted on mice found very interesting results in evidence of this phenomenon. In the study, mice were subjected to a conditioning process where they associated a specific smell with an electric shock, inducing fear. Surprisingly, the offspring and even the grandchildren of these mice exhibited fear responses to the same smell, despite never experiencing the electric shock themselves.

Upon closer examination, scientists discovered that the relevant genes responsible for fear responses were epigenetically modified in the sperm of the parent mice. This suggests that the fear response was transmitted through epigenetic changes in the germ cells, ultimately impacting the behavior of future generations.

This and similar findings highlight the remarkable role of epigenetics in shaping our innate responses to certain stimuli, including fear of predators such as snakes or dangerous situations such as height. It implies that our inherited epigenetic signatures, acquired from our ancestors through evolution, can influence our predisposition to fear certain things, even if we have never personally encountered them in our own lives. Most of us might not have even seen some of these predators in life, yet we are afraid of them by default in our first encounter.

Your lifestyle choices have a profound impact on your health and well-being as well as on your children. Unhealthy habits and exposures can increase the risk of various diseases, including cancer and psychological problems, in both you and your children through epigenetic transmission. This emphasizes the significance of our lifestyle on both our own as well as our children’s and even grandchildren’s physical and mental health. So, think deeper about your eating and exercise habits for your own and your children’s sake!!

Because of its importance, several drugs have been developed or are being developed to target epigenetic readers and writers for different diseases including many cancers.  

There are enormous complicated mechanisms implemented in our genome and epigenome to tightly regulate the state of every single cell in our body. These mechanisms are influenced in every single stage of our development not only by internal cues but also by external factors in our environment. These fine tunings are orchestrated in a manner to benefit the cells, but with the final goal of overall fitness of the organism, and potentially its progeny.

Cell

Throughout the previous chapters, we have explored the mechanisms controlling the genome and how genetic information is translated into functional molecules that drive cellular processes. While a significant portion of gene-related functions takes place within the nucleus, it is important to broaden our perspective and delve into the complexities of the entire cell.

The nucleus, housed within the cell, can be considered analogous to the brain of the cell. It stores memory, information and provides directives for behavior and response, in this case cellular behaviors and cell responses. Drawing a parallel to the human body, one might argue that the brain is the most important organ, responsible for controlling our bodily functions and orchestrating our actions and responses. Similarly, the nucleus holds great importance within the cell, governing essential processes and ensuring the cell's survival and proper functioning. However, it is essential to recognize that just as the body cannot survive without the collective efforts of various major organs like the heart, liver, and lungs, the cell relies on a multitude of organelles to maintain its viability and carry out its functions. Each organelle within the cell has its own specialized role, working in synergy with others to ensure the cell's homeostasis and overall health.

The discovery and understanding of cells revolutionized not only biology but also the broader field of science. Prior to the acknowledgment of cells, our understanding of diseases and their transmission was limited and often misguided. Diseases such as plague and cholera were attributed to airborne factors emanating from decaying matter, with little consideration given to their potential contagious nature and person-to-person transmission. Imagine the profound impact of such ignorance on the spread of diseases!

The development of the microscope marked the initial milestone in the discovery of cells. Microscopes consist of different components, with lenses being a key element, and the use of lenses for magnification dates back to ancient times. Therefore, the invention of the microscope was a gradual process rather than a single event. While it is difficult to pinpoint the exact date of the first microscope use, Antonie van Leeuwenhoek, a self-taught scientist from the Netherlands, played a significant role in advancing the field. His contributions began primarily in the 1660s and 1670s, during which he achieved a remarkable magnification of up to 500 times. This breakthrough allowed him to identify numerous microscopic structures and cells, including bacteria and sperm.

However, cells were first described by Robert Hooke in his book Micrographia in 1665. In the book, Hooke presented and illustrated a wide array of samples that he had examined using a microscope. There, he adopted the term Cell for the structures he was observing in many samples but primarily in plant tissues. It was in this work that he coined the term "Cell" to describe the structures he observed, primarily in plant tissues. The term "cell" was chosen because the structures resembled small rooms or compartments in the plant tissues, reminiscent of a prison cell under Hooke’s eyes. Due to the limitations of the microscopes available to Hooke at that time, he was unable to observe organelles such as the nucleus within the cells. As a result, he did not realize that these structures were dynamic and living entities.

Van Leeuwenhoek's advancements in microscope technology allowed him to achieve higher magnifications, enabling him to observe microorganisms and identify motile creatures. Recognizing that motility is a characteristic of living organisms, he argued that these tiny creatures were in fact living “tiny animals”. This groundbreaking observation contributed to the understanding that cells were living units. However, it took over a hundred years before the concept of cells as the building blocks of plants and animals emerged. There was a general notion among natural scientists that there is a fundamental unit for the life but it was just a notion without any idea what that unit could be. In the period from 1839 to 1855, three German scientists, Matthias Schleiden, Theodor Schwann, and Rudolf Virchow, independently formulated the principles of Cell Theory. These principles stated that cells are the basic structural and functional units of all living organisms and that all cells arise from pre-existing cells. The establishment of Cell Theory marked a turning point in biology and laid the foundation for the field of cell biology, greatly shaping our current understanding of the nature of life.

Cell theory consisted of three main principles:

The first principle stated that all life forms, whether microorganisms, humans, or plants, are composed of one or more cells and their products. This principle encompassed van Leeuwenhoek's observations of tiny animals, the microorganisms, and expanded the concept of life to include these previously unseen microscopic entities.

The second principle emphasized that cells are the most basic and fundamental units of life. This concept recognized that all the functions and characteristics of living organisms can be attributed to the activities and interactions of cells.

The third principle of cell theory had a profound impact on the prevailing belief in spontaneous generation, which held that living organisms could arise spontaneously from non-living matter. The principle stated that cells only arise from pre-existing cells, effectively disproving the concept of spontaneous generation. This was a significant milestone in the advancement of biological understanding, as it provided a framework for the continuity of life and the importance of cell reproduction in the perpetuation of species.

The establishment of cell theory marked a major shift in scientific thought and laid the foundation for modern biology, providing a framework for studying the structure, function, and behavior of organisms at the cellular level.

Cell theory, once only a scientific theory, has now become an established and universally accepted fact. While it faced opposition and skepticism in its early years, subsequent scientific research and advancements have consistently supported and reinforced the principles of cell theory. There was opposing theories and alternative explanations to cell theory in its own time, and they have been scientifically rejected through rigorous scientific investigation and scrutiny. Over time, cell theory has evolved and expanded to incorporate new discoveries and understandings. One significant addition to the principles of cell theory was the recognition of DNA as the hereditary information that is passed down from one generation of cells to the next.

Cell theory's ability to adapt and incorporate new knowledge is a testament to the dynamic nature of scientific inquiry. As new technologies and techniques continue to unravel the intricacies of cellular processes, cell theory remains a fundamental framework for studying the complexity of life at the cellular level.

A major dilemma arises within cell theory when considering viruses! Viruses, in the context of the modern interpretation of cell theory, pose challenges as they differ significantly from typical cells. While currently energy flow and metabolism are considered fundamental features of cells, viruses lack these characteristics. They lack a lipidic membrane like other cells, but they possess DNA or RNA as their hereditary information. Viruses do not directly arise from pre-existing viruses but rather indirectly through the hijacking of host cell machinery. Unlike cells, they do not undergo division, but are subject to natural selection. These unique attributes place viruses on the fringes of life forms, leading to varying opinions regarding their classification. Some consider viruses as life forms, while others do not. Regardless of the debate surrounding the status of viruses within cell theory, they are infectious agents capable of infecting all known life forms on our planet. While viruses challenge certain aspects of cell theory, this does not discredit the cell theory and the broader principles that govern life forms as we currently understand them. Our assurance that all known life forms are composed of cells remains valid, regardless of the debate surrounding the status of viruses. This is a very important caveat that many science deniers, such as evolution deniers, do not comprehend. Bearing the term theory does not mean it is subject to your opinion! Scientific theories, such as cell theory, are supported by extensive evidence and serve as the foundation of our understanding of the natural world. Observations or discoveries that may appear contrary to a theory do not negate the validity of the theory itself. Just as the existence of viruses does not negate the fact that we are composed of cells.

Setting viruses aside, it is indeed true that all terrestrial life forms align with cell theory. The key distinction among cells arises from the presence or absence of a membrane-encapsulated nucleus. Antonie van Leeuwenhoek was likely the first person to observe the nucleus, and subsequent studies confirmed its existence in various species. While the nucleus was visible in many animal and plant samples, it was absent in most microorganisms.

In 1925, a French biologist named Édouard Chatton recognized this distinction and proposed the terms "prokaryotes" for cells lacking a membrane-bound nucleus and "eukaryotes" for cells possessing distinct membranous nuclei. However, Chatton's classification did not gain widespread recognition until 1962 when two other microbiologists popularized it.

Although the nucleus was observed in the early 1800s, its precise role in the cell remained unknown for many years. It was not until 1877 that Oscar Hertwig, a German zoologist, made a significant discovery. Hertwig reported the process of fertilization in sea urchin eggs, revealing that it involved the fusion of the sperm nucleus with the nucleus of the egg. We first learned how animals, including us, are formed through a fertilization process by mixing the sperm and egg’s nucleus in the sea urchin! In 1885, Hertwig also proposed the idea that nucleic acids within the nucleus were responsible for heredity. However, it took several more decades to obtain concrete evidence supporting this hypothesis. It was not until 1944 that an experiment involving rough and smooth pneumonia bacteria confirmed that nucleic acids, specifically DNA, carried the genetic information responsible for hereditary traits.

The presence or absence of a membrane-bound nucleus is not the only distinguishing factor between eukaryotes and prokaryotes. Prokaryotic cells, such as bacteria, generally lack any membrane-bound organelles within their cytoplasm. In contrast, eukaryotic cells, which include plants, animals, fungi, and protists, possess a variety of membrane-bound organelles that serve different functions. In addition to the nucleus, eukaryotic cells contain organelles such as mitochondria, Golgi apparatus and endoplasmic reticulum. The presence of these membrane-bound organelles is one of the key distinctions between the cellular structures of eukaryotes and prokaryotes.

If nucleus is the brain of cells, then mitochondria is the heart. Mitochondria pumps energy to the cells providing the force for all cellular processes. The journey of energy production begins in the cytoplasm, where glucose is broken down into pyruvate during the glycolysis. Pyruvate then enters the mitochondria, where it undergoes the Krebs cycle or citric acid cycle, named after Hans Adolf Krebs who discovered it. He received the Nobel prize in medicine in 1953 for his discovery. The Krebs cycle is a complex series of chemical reactions that extract energy from pyruvate, generating ATP (the cellular energy pockets) and other energy-rich molecules.

During the Krebs cycle, the breakdown of pyruvate releases electrons that are transferred to a chain of proteins in the mitochondria's inner membrane, known as the electron transport chain. As the electrons move along the chain, they generate a flow of protons across the membrane. This creates an electrochemical gradient that drives the synthesis of ATP through a process called oxidative phosphorylation.

The ATP molecules produced in the mitochondria are then transported back to the cytoplasm, where they serve as the energy source for various cellular activities and daily function, including muscle contraction, active transport, and synthesis of molecules. Since the whole cycle requires oxygen, it is called aerobic respiration (Figure 5.1).

Figure 5.1: Left: mitochondria structure; Right: mitochondrial energy production path with Krebs cycle.

Fatty acids can also be used as a source of energy in mitochondria through a process called fatty acid oxidation or beta-oxidation. During this process, fatty acids are broken down into acetyl-CoA molecule, which enters the Krebs cycle to generate ATP. The flexibility of mitochondria in utilizing different fuel sources, such as glucose and fatty acids, allows cells to adapt to varying energy demands. So, either way, mitochondria are the powerhouse of the cell - mitochondrion is the singular form and mitochondria is plural.

The number of mitochondria within a cell can vary depending on its energy requirements. Cells with high energy demands, such as muscle cells or liver cells, tend to have a larger number of mitochondria to meet their energy needs. Some unicellular eukaryotes, like yeast, have only one mitochondrion to fulfill their energy requirements. Meanwhile, different cells in our body have various energy need thus have various number of mitochondria. For instance, mature red blood cells lack mitochondria. This is because their primary function is to transport oxygen, and they rely solely on anaerobic metabolism for their energy needs. On the other hand liver cells can have up to 2000 mitochondria within them to meet their energy needs.

Interestingly, mitochondria are unique organelles with their own semi-autonomous characteristics. The presence of two layers of lipid membrane and their own DNA distinguishes them from other organelles in the cell. This DNA is separate from the nuclear DNA found in the cell's nucleus.

One fascinating aspect of mitochondria is their ability to undergo division, a process known as fission, similar to bacterial division. They have the machinery to replicate their own DNA and divide independently of the host cell's division cycle. This ensures that the new daughter cells receive a sufficient number of functional mitochondria.

The timing of mitochondrial division can be coordinated with the cell cycle of the host cell. In many cases, mitochondrial division occurs prior to the host cell's division, ensuring that each new daughter cell inherits a population of mitochondria. However, it's important to note that the exact timing and coordination can vary depending on the energy demands and requirements of the host cell.

The structure and characteristics of mitochondrial DNA, as well as the presence of their own ribosomes, provide strong evidence for the endosymbiotic theory. Mitochondrial DNA is a small, circular molecule, similar to the DNA found in bacteria, rather than the linear DNA found in the nucleus of eukaryotic cells. The ribosomes within mitochondria, known as mitochondrial ribosomes or mitoribosomes, bear a striking resemblance to bacterial ribosomes in terms of their size, shape, and structure. This similarity suggests a shared ancestry between mitochondria and bacteria.

Furthermore, the protein translation system within mitochondria exhibits similarities to the prokaryotic translation system rather than the eukaryotic translation system. This includes the presence of specific proteins on the mitochondrial membrane that are absent in eukaryotic cells.

Additionally, certain types of lipids found in the inner mitochondrial membrane resemble those found in bacteria. These similarities in DNA, ribosomes, protein translation, and lipids provide compelling evidence for the endosymbiotic theory.

Endosymbiotic theory states that certain organelles found in eukaryotic cells, such as mitochondria, were once free-living prokaryotes. Through a process known as endocytosis, early eukaryotic cells engulfed these prokaryotes, establishing a symbiotic relationship.

The engulfed prokaryotes, which eventually became the pre-mitochondria, were able to provide a valuable energy source for the host cells. This mutualistic relationship enhanced the survival and reproductive success of both the prokaryotes and the host cells. The formation of the double lipid membrane structure of mitochondria can be explained by the process of endocytosis.

The pre-mitochondrial bacteria had a single-layer lipid membrane, similar to that of bacteria. When they were engulfed by the early eukaryotic cells, the host cell's lipid monolayer surrounded and encapsulated the pre-mitochondria, resulting in the formation of two lipid membranes. This process of enveloping and internalizing materials from the environment is known as endocytosis, which is a common mechanism used by eukaryotic cells to eat-up stuff from their environment.

The similarities in the composition of lipids and proteins found in the inner lipid membrane of mitochondria and bacteria further support the endosymbiotic theory. These similarities indicate a shared evolutionary history between mitochondria and bacteria, and they provide evidence for the integration of a once-free-living prokaryote into the eukaryotic cell.

The emergence of the endosymbiotic theory can be traced back to the early 1900s. However, the accumulation of evidence, as mentioned above and from other sources, has significantly strengthened the theory, leading to its universal acceptance that mitochondria have a prokaryotic origin. This same theory applies to the origin of chloroplasts, which are organelles found in plant cells responsible for photosynthesis. Like mitochondria, chloroplasts are believed to have evolved from free-living prokaryotes through a process of endosymbiosis.

The bacteria known as Cyanobacteria, or blue-green algae, are capable of performing photosynthesis and harnessing energy from sunlight. The pre-eukaryotic cells that engulfed these photosynthetic bacteria established a symbiotic relationship, leading to the incorporation of the Cyanobacteria as chloroplasts within the host cells.

The endosymbiotic theory explains the high degree of similarity between chloroplasts and Cyanobacteria. Chloroplasts possess their own DNA and ribosomes, similar to bacteria, and their inner membrane structure and composition resemble that of Cyanobacteria. These shared characteristics provide evidence for the evolution of chloroplasts from a prokaryotic ancestor.

The pre-eukaryotic cells that engulfed pre-mitochondrial bacteria eventually became animal eukaryotic cells, while those that also incorporated pre-chloroplast cyanobacteria developed into plant eukaryotic cells (plants possess both mitochondria and chloroplasts).

There are hypotheses suggesting that other membranous organelles, such as the nucleus, endoplasmic reticulum, and Golgi apparatus, may also have originated from endosymbiotic prokaryotes. However, the evidence supporting these hypotheses is not as robust as that for mitochondria and chloroplasts. As a result, they do not fit as neatly into the endosymbiotic theory and are not widely accepted within the scientific community.

Anyways, there is a famous statement saying “life did not take over the globe by combat, but by networking”. May that be a lesson to the countries and societies!

The endoplasmic reticulum (ER) is another membranous organelle found in many eukaryotic cells. It can be classified into two types: rough endoplasmic reticulum (RER) and smooth endoplasmic reticulum (SER). The rough endoplasmic reticulum is characterized by the presence of ribosomes on its surface, giving it a rough appearance under a microscope. In contrast, the smooth endoplasmic reticulum lacks ribosomes, resulting in a smoother appearance.

The endoplasmic reticulum is closely associated with the nucleus and is continuous with the nuclear membrane. It plays a crucial role in protein synthesis and processing. Polypeptide chains, which are synthesized by ribosomes, enter the rough endoplasmic reticulum, where they undergo further modifications and folding to attain their functional, three-dimensional structure. This process is essential for the production of mature and fully functional proteins.

In addition to protein synthesis, the smooth endoplasmic reticulum is involved in other cellular functions. It participates in lipid synthesis, including the production of various types of lipids such as phospholipids and steroids. The smooth endoplasmic reticulum is also responsible for the detoxification of certain substances within the cell such as cellular waste, including alcohol. For example, in liver cells, which have a particularly high abundance of smooth endoplasmic reticulum, it aids in the detoxification of consumed alcohol and other harmful compounds.

The unique functions of the endoplasmic reticulum highlight its significance in cellular processes and overall organismal health. The rough and smooth types of endoplasmic reticulum work in coordination to ensure proper protein synthesis, modification, and lipid metabolism, contributing to the overall functionality of eukaryotic cells.

The Golgi apparatus is the last permeant and essential membranous organelle found in our cells. It consists of several flattened layers of lipid membrane that are typically located adjacent to the endoplasmic reticulum. The Golgi apparatus plays a crucial role in protein processing and sorting within the cell.

Proteins that are synthesized in the endoplasmic reticulum are transported to the Golgi apparatus, where they undergo further modifications and receive molecular tags that determine their final destination. Golgi apparatus acts similar to a post office, where it functions as the cellular sorting and packaging center. It receives proteins from the endoplasmic reticulum and adds specific molecular tags to them, which serve as "addresses" indicating where the proteins should be sent, especially those that need to be secreted outside of the cell.

The discovery of the Golgi apparatus is credited to an Italian scientist named Camillo Golgi, who first described this organelle in 1897. In recognition of his contribution, the organelle was named after him.

The Golgi apparatus plays a vital role in maintaining the proper functioning of the cell by ensuring that proteins are correctly processed, modified, and sorted to their appropriate destinations.

In addition to the permanent membranous organelles, cells also contain various transient membranous organelles involved in the transportation of molecules. One prominent example is vesicles, which play a crucial role in the intracellular transport of diverse molecules. Vesicles are small, spherical structures enclosed by a lipid bilayer membrane. They serve as cargo carriers, shuttling different molecules within, into, and out of cells. The contents of vesicles can vary widely, ranging from hormones, enzymes, ions, to metabolites. These vesicles are involved in various cellular processes and have distinct functions depending on their type.

Exosomes are a type of vesicle involved in the export of materials from cells. They are responsible for releasing certain molecules, such as signaling proteins or genetic material, to the extracellular environment, allowing intercellular communication.

Endosomes are vesicles that participate in the uptake of incoming molecules into cells. They act as a sort of "entry point," facilitating the internalization of substances from the extracellular space. Endosomes play a role in processes such as receptor-mediated endocytosis, where specific molecules are engulfed and transported into the cell.

Vacuoles are storage organelles that can also function as vesicles. They can contain a variety of molecules, including water, ions, and nutrients. In plant cells, vacuoles are particularly important for maintaining turgor pressure and storing various substances such as pigments and toxins. Lysosomes are specialized vesicles that function as the "cellular stomach." They contain digestive enzymes capable of breaking down different types of molecules, including proteins, lipids, and carbohydrates. Lysosomes are involved in the degradation and recycling of cellular components, as well as the digestion of engulfed materials such as food particles or cellular debris (Figure 5.2).

Figure 5.2: Different types of vesicles moving in the cells and transferring material to from one compartment to another.

The discoveries related to vesicle trafficking and its significance as a vital transport system in cells were recognized with the Nobel Prize in Physiology or Medicine in 2013. This award highlighted the fundamental understanding of how vesicles facilitate the movement of molecules within cells, contributing to various physiological processes and cellular communication

Membranous organelles are not the only contributors to cellular maintenance. There are many other major players which are not encapsulated by lipids, one such major player is the cellular Cytoskeleton. The cytoskeleton is a vital component of cellular architecture and function. It is a complex network of protein filaments that extends throughout the cell, providing structural support, facilitating cellular movement, and playing a crucial role in various cellular processes.

The cytoskeleton is composed of three main types of protein filaments: microtubules, intermediate filaments, and actin filaments (microfilaments).

Microtubules are hollow, tubular structures made up of the protein tubulin. They are involved in a wide range of cellular functions, including cell shape determination, intracellular transport of organelles and vesicles, and the formation of structures like cilia and flagella. Microtubules also play a crucial role in cell division, forming the mitotic spindle that segregates chromosomes during cell division.

Intermediate filaments provide mechanical stability to the cell and are particularly important in tissues subjected to mechanical stress, such as epithelial cells and muscle cells. They contribute to the maintenance of cell shape and integrity, as well as anchoring organelles within the cell.

Actin filaments, also known as microfilaments, are thin, flexible filaments composed of the protein actin. They are involved in numerous cellular processes, including cell movement, cell division, and the formation of cellular protrusions like microvilli. Actin filaments play a significant role in muscle contraction by interacting with myosin proteins (Figure 5.3).

Figure 5.3: Muscle cells are stained for their nucleus (blue) and actin filaments (yellow).

The cytoskeleton is responsible for the distinctive shapes and structures of different cell types. For example, neuronal cells possess long, branched extensions called dendrites and axons, which are supported and guided by the cytoskeleton. Muscle cells have highly organized arrays of actin and myosin filaments that enable their contractile properties.

Moreover, the cytoskeleton is dynamic and can undergo rearrangements in response to various signals and stimuli, allowing cells to adapt to their environment and perform essential functions.

Coordination of all these organelles and their functional outputs require tightly regulated communications among them. These processes respond to demands within the cell and demands received from outside of the cell. The whole process of cellular inter and intra-communication, and adaptation to microenvironmental changes, is collectively called Cell Signaling. Cell signaling can occur in various ways, such as inside the cell (Intracrine), outside the cell and acting on the same cell (Autocrine), among neighboring cells only (Juxtacrine), and even among nearby cells (Paracrine) or very distant cells (Endocrine).  

To maintain homeostasis and adapt to environmental changes such as light, stress, hunger, smell, or even ideas that provoke thoughts and neuronal processes, our cells receive cues and strive to coordinate with involved organs in order to respond appropriately. These cues are received by specialized proteins called receptors. Receptors are primarily proteins that have a three-dimensional structure perfectly suited to bind to specific signaling molecules, such as smell molecules or hormones. While receptors are typically found on the cell surface, they can be present anywhere in the cell depending on their function.

When a signaling molecule binds to its receptor, it is akin to a key fitting into a lock. This interaction induces structural changes in the receptor, which are sensed by other proteins through a similar key-lock mechanism. This process involves multiple proteins in a signaling cascade, ensuring the highly regulated transmission of signals. Cells constantly receive a wide array of signals, necessitating the need for precise regulation. The signaling cascade ultimately activates proteins that are for example involved in gene expression, leading to adaptation to the new changes.

The involvement of multiple proteins in the signaling cascade allows for intricate regulation and fine-tuning of cellular responses. This complex network ensures that cells can appropriately interpret and respond to the diverse signals they encounter. By activating specific proteins, such as those involved in gene expression, cells are able to orchestrate adaptive responses to maintain homeostasis and effectively respond to environmental changes.

For example, let's consider the sensation of smell. When a smell molecule binds to its receptor in the cells of our nose, it sets off a cascade of protein-protein interactions. Eventually, an effector protein is activated, which opens up cellular pumps, allowing ions to flow in and out of the cell. This ion movement in neural cells generates an electrical pulse, which then sends a signal to the brain, allowing us to sense the smell. In 2004, Linda B. Buck (Figure 5.4) and Richard Axel from US won the Nobel prize in medicine, “for their discoveries of odorant receptors and the organization of the olfactory system”.

Figure 5.4: Linda B. Buck, Nobel laurate of 2004

Cell signaling represents a significant frontier in biological studies. Researchers worldwide focus on unraveling different signaling cascades to decode how specific biological processes occur, ranging from development and tissue repair to immunity and sensation. Given that cellular interaction via signaling is a fundamental aspect of biological systems, perturbations in signaling pathways can lead to various diseases. Conditions such as cancers, immunological disorders, diabetes, neural disorders, and developmental disorders often arise from alterations in cellular signaling.

The study of cell signaling and its dysregulation has garnered considerable attention and recognition in the scientific community. Numerous Nobel Prizes have been awarded for groundbreaking research in different signaling pathways associated with diverse physiological functions. For instance, the Nobel Prize in 2019 was awarded for elucidating the signaling cascades that regulate oxygen sensing in cells. These advancements not only enhance our understanding of cellular communication but also offer potential avenues for therapeutic interventions in the treatment of diseases.

In a multicellular organism, every cell engages in extensive communication with other cells while also maintaining its own internal balance, known as homeostasis. Numerous signaling cascades are simultaneously at play, working together to coordinate the cellular status and its contribution to the overall functioning of the organism. This complex network of signaling pathways ensures that cells can rapidly and accurately multitask.

One key aspect that aids in the efficiency of cellular communication is the compartmentalization of activities within different organelles. Each organelle has specialized functions and houses specific signaling molecules, allowing for targeted and regulated processes. Moreover, the spatiotemporal organization of molecules within cells plays a vital role. Molecules are strategically positioned within the cell to enable rapid interactions and response times, ensuring precise coordination of cellular activities.

This sophisticated system of communication and organization within cells allows for effective coordination of functions, even in complex multicellular organisms. By harmonizing the activities of individual cells, the organism as a whole can maintain homeostasis and carry out essential physiological processes.

Prokaryotic cells, in comparison to eukaryotic cells, exhibit a simpler intracellular compartmentalization due to their less complex functions. Prokaryotes are predominantly unicellular organisms, although some may form multicellular structures. However, these structures do not constitute a complete individual organism but rather exhibit cooperative interactions. Consequently, the communication systems in prokaryotes are less intricate, as they do not require the level of complexity observed in eukaryotes.

Nevertheless, the process of endosymbiosis presented significant opportunities for certain pre-eukaryotic cells. Through the incorporation of symbiotic relationships with other cells, these pre-eukaryotic cells gained access to new functionalities and capabilities. This, coupled with the evolution of cooperative communication mechanisms, eventually led to the development of multicellular eukaryotic organisms.

The combination of endosymbiosis and the transition from cooperative communication to organismic organization served as a catalyst for the emergence of complex multicellular life forms in the eukaryotic lineage. This evolutionary trajectory allowed for the specialization and coordination of various cell types and functions, resulting in the diverse array of multicellular organisms seen today; all starting from the Cells.

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