The first is the preservation of characteristic, long term data imprints that describes the development of an organism in the stable DNA sequences.

Second is the storage of medium term epigenetically featured data that is carried a couple of generations further down the cellular level. Epigenetic information is not stored within nucleotide sequences but in the chemical modifications of these sequences (like the methylation of repeated strings of GC dinucleotide).

Third is the storage of data generated as a result of dynamic interactions between proteins, RNA and DNA in order to adapt to the events and changes during cellular life cycle in the form of nucleoprotein or DNA-protein complexes.

The data generation and storage capacity of DNA in three different hierarchical levels and time periods demonstrates that genome plays a plethora of roles in cellular activities and heredity. Formatting of genome for its generation and storage of data is carried out via DNA sequences of various features. Genomic system is composed of repeating DNA sequences. DNA sequences (satellite) function as a marker as they repeat numerous times in various frequencies. Genome includes genomic folders similar to that of computer systems. These genomic folders, also known as the epigenetic index of genomes, are responsible for the remodeling of chromatin and the coordinated control of genomic functions. Repeating DNA sequences play a critical role in replication of genome (making a copy of DNA), dispersal of copied DNA into daughter cells and construction of support systems that enable organization of chromatins.

It is possible to better understand genomic functions in relation to examples such as memory sticks and hard drives that are used in electronic information systems. The difference between a genome as a basic data-information storage medium from a hard disc is that it can be replicated as required by its nature and these replicas can be transferred to daughter cells. Following examples could be given to illustrate that a genome gains function only when it interacts with various data processing modules in the cell.

1. A copy of genome is produced by cellular DNA replication system
2. Correct localization of each genome copy towards daughter cells is only possible when chromosome segregation system works (the centrosomes and microtubules)
3. The central transcription system is responsible for the copy of data from DNA to RNA. Different gene expression patterns are developed via regulation of transcription time and level with the help of transcription factors and a web of cell signalization.

Very intricately organized genomic system structures are designed through the successive combination of protein encoding sequences, signals distributed in various places and repeating DNA sequences. Formatting of genome resembles formatting of computer programs. Various repeated serial commands of computer software are used to allocate addresses to files independent of the original data contained; different computer systems use different signals and structures to manage programs. In a similar fashion, diverse living species often utilize repeating DNA sequences and chromosomal structures to organize the encoded information and to format their genomes.

Diversity and variation of repeating DNA sequences are building blocks that are constructed into different genomic system structures. Genomes of different organisms bear characteristic system morphology just like computers with various operating systems and hardware. For instance, animal cells are created as a good model to take and incorporate foreign DNA into their genomes. Genetic data transfer among organisms of the same kind is referred to as “vertical gene transfer” whereas transfers between different species, genuses and classes are called “horizontal gene transfer.” Mobile DNA sequences like transposons are very effective horizontal gene transfer agents.

Cellular differentiation and morphogenesis (formation of tissue and organ from cell) is not programmed completely in the primary structure of the DNA sequence. Components of modular programs are encoded in a flexible way and a continuous renewed and recombined arrangement is enabled when needed.

The reason behind creation of different organisms from a single genome is this utilization of such genomic structure. Metamorphosis, that is the development of different organisms like invertebrates such as a caterpillar and a butterfly, is a good example of this feature.

Two organisms from the perspective of the same genomic protein and RNA codes can be considered as two different species. Different genomic structures and repetition of sequences among different organisms are distinctive criteria for the identification of species since these features can lead to mismatch of reproductive cells, different expression patterns of genetic code sequences, and may cause ecological diversity as well. That is why repeated DNA sequences are very important in studying parental relationships. Today, microsatellite DNA as repeated DNA sequences are used to configure biological relations among individuals in forensic sciences. Plant species vary in respect to the repeated sequences in centromeres in their chromosomes; these variations are used for identification of species. Main determinants of genomic system structure are diversity, frequency, and genomic localization of repeated DNA sequences. To explain this with examples, we could say that successively repeated sequences at centromeres, telomere repetitions and transcription, packing of chromatin, repeated sequences that are spread throughout genome in charge of cellular functions like nucleus localization are the main elements of the genome system structure. Genome is a single integrated system that is controlled closely and remotely via communication webs that use repeated sequences.

While explaining the Qur’anic concept of the Manifest Record (36:12) Bediuzzaman Said Nursi, the great renovator of Islamic thought in Turkey in the twentieth century, wrote that the Manifest Record expresses one aspect of Divine knowledge that is related “more to the past and future than to the present. It is a book of Divine Destiny that contains the origins, roots, and seeds of things, rather than their flourishing forms in their visible existence” (30th Word, Second Aim).

Inspired from this view, a seed can be considered as a tiny adorned form of Divinely creative command as programs and indexes and as a determinant for those programs and indexes in the organization of an entire tree. Since the Manifest Record book, as a title of Divine knowledge and command, observes the past and the future rather than the present, the genome of a grain or a seed acts like a library and an archive in which the future and past of an organism is written.

Sequences encoding different information in DNA

Different information types corresponding with various DNA sequences exist in the genome. These DNA sequences that were considered junk for a long time because they were not coding proteins, have in fact been found to be responsible for an amazing array of functions in genomic structure. Some of these sequences include:

1. Group determining sequences that enable coordinated or successive expression of genes,
2. Sequences acting as a marker in charge of initiation and termination during transcription of DNA to RNA ,
3. Signal sequences responsible for conversion of primary immature RNA, sequences into smaller functional RNA molecules,
4. Transcription control sequences that determine the expression frequency of genes,
5. Sequences that identify and mark the initiation regions for intensification and remodeling of chromatins,
6. Sequences that make binding regions which affect the relocation of genome in nucleus or nucleolus,
7. Sequences that target regions where covalent DNA modification (methylation) with functional groups like methyl takes place,
8. Sequences that control and identify the regions responsible for initiation of DNA replication,
9. Sequences that make the structures which enable completion of replication at terminal ends,
10. Sequences at the segregation points that enable equal distribution of copied DNA molecules into daughter cells and centromere sequences,
11. Sequences responsible for guidance during repair of DNA bound errors and damages,
12. Start point sequences used for repackaging of genomes,

Recurring sequences exist in the genomes of many organisms and shows great structural diversity. Recurring elements function as an initiator or terminator for heterochromatin regions. Furthermore they form an important scaffold and binding spots for folding of DNA structure. As if they carry out the job of an architectural mold in specific shaping of genome to be packed into a very limited area. The ratio of repeating sequences in genome (60-90%) is much more than sequences that are encoding proteins and RNA (10-40%). To explain it with an example, chromosomes in human genome are made up of packages of protein-DNA such as heterochromatin and euchromatin. Heterochromatin regions usually make up the regions with no transcription whereas euchromatin regions feature DNA transcription.

The ratio of protein encoding sequences to the entire human DNA is approximately 1.2%. Around 43% of euchromatin regions are composed of recurring and mobile DNA elements. 18% of heterochromatin region is also made of satellite (dense repeating sequences) and mobile DNA elements. Therefore almost 50% of human genomic DNA is composed of these repeating DNA sequences. In bacteria however, these only make up around 5-10% of the genome. These sequences were described as parasitic and junk individual DNA structures up until today and still continues to be described thus by many researchers and scientist. Nevertheless, even today, mobile DNA elements and repeating sequences are accepted as genomic parasites. Recent advances in the last ten years that have demonstrated this is not true, have instead revealed the vital importance of repeating sequences in genomic functions.

Repeating DNA sequences affect chromatin (dense pack of DNA and protein) structure in two ways. Irregular repeating DNA sequence copies contain binding regions for proteins that organize DNA. Heterochromatin (darker since it is densely packed chromatin) inhibits transcription and recombination, delays replication, and generally blocks the reading of information in DNA sequences that contain genetic coding. Heterochromatin regions are distributed throughout the chromosome. Because of this, presence of regions with coupled successive repeated sequences triggers heterochromatin formation.

In fruit flies, placement of protein encoding loci required for eye pigmentation near the heterochromatin blocks in centromeres (phenomenon of position effect) is provided via organization of chromosomes and thus, formation of phenotypic characters are inhibited. The “phenomenon of position effect” is convincing evidence that genome is a major system which is integrated with composition of partially repeating DNA sequences. When heterochromatin amount is increased in XYY male fruit flies, reorganized pigmentation of eye expression decreases. In XO males, when heterochromatin amount decreases, inhibition becomes severe. Changes in levels of protein which binds to special heterochromatin specific DNA regions generate opposite effects. Decrease in these proteins reduces or suppresses “phenomenon of position effect.” Surplus synthesis of these proteins also enriches this effect.

Repeating DNA sequences play an important role in the transfer of genome into daughter cells. For instance, they function in formation of the centromeres as chromosomal binding regions for microtubules, during gamete formation as linear terminals of chromosomes are replicated, and during chromosomal matching. Distribution of repeating sequences plays a major role in configuration of genomic functions. Each genome has genomic system structure that is shaped dependent on the amount of repeating DNA sequences to a major extent.

Going back to Nursi’s explanation of the Manifest Record, we can draw a parallelism between the book of the universe and the book of revelation, the first of which shows us that certain sequences in the genome are repeated for significance and necessity, just as many verses are repeated frequently in the Qur’an with nuances to refer to different meanings, benefits, and purposes, opening a wider space for many interpretations.

A genome is not only a book that contains protein and RNA codes, but also has a complex system structure with many functions for cellular vitality. The most needed sequences are those that are repeated more frequently. They are not pieces of junk DNA as predicted, they are jewels Divinely constructed.

References

• Shapiro J. A. 2001. “Genome Formatting for Computation and Function :Genome Organization and Reorganization in Evolution: Formatting for Computation and Function.” Presented at a symposium on “Contextualizing the Genome,” Ghent University, Belgium, November 25 – 28, 2001 (Ann. N.Y. Acad. Sci., in press)
• Shapiro, J.A. 2005. “A 21st century view of evolution: genome system architecture, repetitive DNA, and natural genetic engineering.” Gene 345, pp: 91–100.
• Shapiro J. A. and Sternberg R. V. 2005. “Why repetitive DNA is essential to genome function.” Biol. Rev., 80, pp. 1–24. Cambridge Philosophical Society.

Spending so much time in the library for a particular book further amazed me about the answer I was searching for in my research. I am trying to understand how our genome is organized and how it functions. In order to make myself clear, let me first try to explain what the genome is. I bet you will be amazed by the impressive genome organization and its flawless function, too.

The genome can be thought of as a library. Each book in the “genome library” is what we call a “gene”. Every gene is different in size and the information they contain, just like the books in the library. Like the different sections in the library, our genes are also compartmentalized into different chromosomes. We have 23 pairs of chromosomes. One pair contains the information from our father and the other one from our mother. Therefore, unlike libraries, where you may find more than one copy of a book, our genome has two copies of each gene (except the genes on the X and Y chromosomes which carry only one set of genes).

Every cell in our body carries its own library: the genome. Our genome is the smallest library in terms of physical volume, yet contains relatively the largest amount of information. In our body, which contains roughly 100 trillion cells, we carry 100 trillion of these libraries. Here comes the amazing part; each of these libraries contains 3 billion letters of information. If this information were to be printed, it would take 1000 books of 200 pages each. The information in our genome is coded by a 4 letter alphabet; Adenine (A), Guanine (G), Cytosine (C) and Tymine (T). These four letters (A,G,C,T), called deoxyribonucleic acids, are the building blocks of every DNA strand on earth. The collective amount of these letters in any organism constitutes of its genome. We, as humans, have about 3 billion of these letters in our genome, which is encapsulated in the nucleus of every cell in our body. The total length of our genome is 2 meters long. This 2 meter long stretch of DNA (3 billion letters of information) is highly compacted and packaged in the nucleus, which is only 2 micrometer in diameter, an amazing 1,000,000 fold compaction!

How is our genome, which is 2 meters long, compacted so much that it fits in a nucleus only 2 micrometer in size? In the nucleus, DNA is wrapped around a group of 8 proteins called histones. This combination of DNA and histone proteins forms a special structure called “beads on the string”. Each bead is called “nucleosome” (Figure 1).

Multiple nucleosomes are then coiled together and stacked on top of each other. This organisation further packs the DNA up into a thicker fiber called “chromatin”. This chromatin fiber further condenses by forming tight loops. The structure which we call a “chromosome” is actually the most compact form of the chromatin fiber, which is only visible under the microscope during cell division. This remarkable chromatin organization allows a 2 meter long DNA to fit into the nucleus of each cell, an object so small that 10,000 of these nuclei can fit on the tip of a needle!

This remarkable genome organization further impresses us when we think about the utilization of this genetic information by over one hundred trillions of cells in our body. These many cells in our body are not all similar to one another. Most of the cells in our body are specialized to carry out specific functions. We have more than 200 different cell types specialized for unique functions. Some cells, like B and T cells in our immune system, are dedicated to fighting against infectious agents, whereas other cells, like neurons, function by transmitting signals between our brain and muscles. Since these cells have different structures and carry out different functions, they require different sets of instructions coded by genes in the genome. There are roughly 20.000 genes in our genome. Importantly, each specialized cell in our body utilizes only a subset of these genes, not all of them, at any given time. In other words, from the library analogy, roughly two third of the books (i.e., genes) are needed for each cell to function. The remaining one third of the genes is not necessary for that particular cell type. For example, the MYOD1 gene encodes a protein required for muscle cell differentiation. Therefore, this gene is absolutely required for muscle cells. However, the same gene is not required for the B or T cells that function in our immune system. While the MYOD1 gene has to be stored in an easy access location (open chromatin) for muscle cells, immune cells do not need this gene, and therefore it is stored in the depository section of the “genome library” (closed chromatin), which is not used very often.

In line with this, each cell has to organize its genome in a special way so that the genes needed for its function should be easily accessible. This remarkable genome packaging and organization allows each cell to easily and very quickly access the required genes for transcription into the proteins. On the other hand, those genes that are not going to be used are stored in relatively inaccessible regions in the genome library. Therefore, the genome is not packaged similarly all along. Certain regions of the genome are “open” and therefore easily accessible (called euchromatin) for transcription, while other regions are kept “closed” by condensed and packed structure (called heterochromatin). Since each cell type requires different set of genes, the genome is also differentially organized between cell types. Genome organization in a muscle cell is remarkably different than genome organization in, let’s say, a skin cell.

After all these explanations, I hear you asking, “How does each cell in our body know how to organize their genome? How does, lets say, a muscle cell decides to become muscle but not a blood cell?” These are exactly the same questions that many scientists are asking nowadays. Since the completion of the Human Genome Project (HGP)1,2, which determined the entire sequence of information of our DNA, scientists have been trying to understand how this amazing alphabet is being used in each and every cell in our body. Francis Collins, one of the great scientists of our time and the current director of National Institute of Health (NIH-USA), is especially noted for his landmark discoveries of diseases associated genes, as well as his leadership in the Human Genome Project. He calls the information coded in our DNA the “Language of God” in his recent book.3 Recent technological advancements allow scientists to better study the structure and function of this language and get better clues about the organization of this genomic library.

Whether we believe that this genomic information is “the language of God” or not, we are closer than ever to understanding the codes of this amazing language. New technological advancements allow us to get better insights about the organization and utilization of this information. The more we learn about it, the more we are amazed about not only its flawless packaging but also its differential utilization in each cell. At any time and in any tissue, trillions of cells are using different sections of the genome library to get the necessary instructions decoded from “the Language of God” and continue their journey in our bodies without any conscious decision making on our part.

Ahmet Mir Fazil holds Ph.D. degree in molecular Biology. He is a research scientist in Boston.

References

1. International Human Genome Sequencing Consortium (2001). “Initial sequencing

and analysis of the human genome.” Nature 409 (6822): 860–921.

2. Venter, JC, et al. (2001). “The sequence of the human genome.” Science 291

(5507): 1304–1351.

3. Francis S. Collins. 2006. The Language of God: A Scientist Presents Evidence for Belief. Free Press.

Original Article: Gibson, D.G. et al., Science Express (2010).

A team of genome researchers at the J. Craig Venter Institute in the U.S recently announced that after almost 15 years of work and with a budget of $40 million, they had finally built the first bacterial strain with a completely synthetic genome. In the study, researchers chopped the genome of Mycoplasma mycodies into 1,000 pieces in the computer, chemically synthesized these fragments and assembled them into an artificial chromosome in yeast cells. The reconstructed artificial genome was subsequently transferred to a closely related bacterium Mycoplasma capricolum, whose genome was removed. Remarkably, the strain with the artificial genome was able to guide the protein machinery of the host cells, produce the necessary enzymes and macromolecules for a bacterium to survive and most importantly to grow and divide. Team leader Prof. J. Craig Venter, best known for his pioneering efforts in human genome mapping project, commented on their findings as “we created a ‘synthetic cell’ and it is the first self-replicating species we’ve had on the planet whose parent is computer.” Many media sources also publicized the study as the first successful creation of the artificial life. As much as the scientific community agreed that the synthesis, transfer and retention of a functional synthetic genome is a breakthrough, most of the scientists have found Prof. Venter’s comments and the media’s reflection on the study to be somewhat of an overstatement. It would be quite unfair to call the new bacteria an example of “artificial life.” The synthesized genome was a copy of another living bacterium with slight modifications. The genome is a blueprint, whereas the proteins perform the actual cellular functions. This new approach shows that we can copy the book of cellular blueprints reliably but it brings no new parts to our inventory. Moreover, the synthetic genome had to be assembled in live yeast cells, processed with biochemical extracts from mycoplasma cells and finally transplanted into another (closely related) live cell. In other words, “natural life” was absolute prerequisite for the so-called “artificial life.” The generation of a fully functioning organism directed by machine-synthesized genome certainly represents a major step in our ability to manipulate large chunks of genetic material. It is clear that this study will positively influence many scientists, especially synthetic biologists, to try writing novel “synthetic” software to recruit the variety of organisms’ cellular hardware for solving various global problems like energy shortage or environmental pollution. However, the philosophical questions that probe the essence of life, like: “Can we reduce life to material? Is the human being ever going to be able to build a live cell from only a few chemicals?” will likely remain as major controversial issues for many years in the age of molecular biology.

2- Sharing the powers of Spiderman

Original Article: Vogel, M.J. & Steen, P.H., PNAS (published online before print on February 4, 2010).

The adhesive powers of Spiderman, jumping from one building to another and walking on the walls, attracted most of our interests. The recent invention of scientists from Cornell University brings this power from science fiction cartoons/movies to the real life. Inspired from a little creature, leaf beetle, which can stick to leaves by generating a force exceeding 100 times its body weight, these researchers designed a device which can stick to surfaces by using the adhesive powers of water. The device consists of a plate not thicker than a credit card with hundreds of tiny holes on it. The water is pumped through these holes, which builds liquid bridges between surfaces and thus generates a strong adhesive force. Simply pushing back the water un-sticks the device in a controllable and switchable manner. There are no solid moving parts nor any kinds of glue used in the system, and this makes device even more promising. The capabilities of the device are not at the level of the leaf beetle yet, but the inventors believe that it can be improved by building on the same principles. The system can potentially be used in many practical applications, such as robotics, and it can also be implemented into shoes and gloves allowing them to stick to surfaces. Accordingly, it is no longer improbable to imagine sharing the sticky-powers of Spiderman and walking on the walls very soon.

3- Igniting a Supernova

Original Article: Gilfanov, M. & Bogdan, A., Nature 463, 924 (2010).

upernova: the Rosetta stone that may help us put together the missing pieces of the cosmic jigsaw puzzle; one of the most energetic and most luminous explosions in the universe, putting out energies equivalent to what our sun could produce in 10 billion years. Yet the mechanism that produces these explosions still eludes us. Once our sun consumes its remaining fuel in another 5 billion years, it will shrink into a “white dwarf.” These compact stars are believed to produce subsequent explosions leading to supernovas if they reach beyond a critical limit of mass. One way to gain mass is to steal material from a companion star through an “accretion” process. Accretion was thought to be the most common means that might help push the mass of a white dwarf beyond the critical mass limit, until a recent study revealed that two clashing (in-spiraling) white dwarfs might be the missing fuse that ignites supernovas. German astronomers measured the X-ray flux of four nearby elliptical galaxies and the core of the Andromeda Galaxy to see whether the amount of X-rays from these galaxies are consistent with predictions based upon the accretion mechanism. Contrary to expectations, the observed X-rays were 2–3% of the amount that would have been produced if accreting white dwarfs were the primary trigger of supernova explosions. Hence, perhaps merging white dwarfs are more commonplace in the cosmos after all.

4- Strategy of bats finding their way

Original Article: Yovel Y et al., Science 327, 701 (2010).

Bats, dolphins, shrews and swiftlets use sound waves for navigation and hunting. They emit short sonar pulses and listen to the echoes reflecting back from solid objects. Microsecond differences in the arrival times of echoes are coded by detector neurons and used as a main cue for positioning objects in an environment. This phenomenon is known as biosonar. A recent study published in Science reveals one unknown part of this perfect sound processing strategy. The study shows that bats do not center the sonar beam on the target. Instead, they aim to match the maximum slope of the beam to the target in order to increase the signal-to- noise ratio. Around the sharp edge, small variations of the target position can be detected as a clear signal change in reflected sound intensity. Furthermore, the researchers showed that if the environment is very noisy, bats could bias this critical point to increase amplitude of the echoes. This powerful technique has already been employed by humans in engineering and used in various technological tools such as atomic force microcopy. Whether this strategy is used in general by other echolocating animals remains to be answered.

Decisions within the cell: mathematical and algorithmic character

In order to enable Escherichia coli bacteria to use lactose (disaccharide), the genetic information of the enzymes that have role in transporting the lactose into the cell and converting it into glucose is coded in the bacteria’s genome. The binding and decoding structure which enables the genes to be transcribed at the right time in the appropriate amount is called the operon. The operons are model mechanisms which work on the synthesis or destruction of every chemical molecule (metabolite). One of these, lactose operon, is a good example that demonstrates how the decoding information contained in DNA is regulated and controlled in the bacteria. E. Coli is equipped with a system that distinguishes lactose and glucose when they are combined and this system functions perfectly. Primarily, all of the existing glucose is consumed before the start of the production of those enzymes that splits lactose into glucose and galactose. It has been discovered that this operation in the bacteria is followed by an interaction between DNA sequences located on the upper part of the lactose gene and various molecules. The DNA sequences on the upper part of the gene are the signals that format DNA for transcription. These signals cause the decoding of the genes that interact with the transcription factors. While some of the signals in the relevant region of the genes are common in most genes, some others are specific.

The most basic interaction system of the genome-proteome (all proteins in cell) is the suppression of the lactose operon that is observed in E. Coli. This process depends on DNA-protein interactions which are based on a mutual relationship and it requires the existence of repeated DNA sequences. Tetramer lac1 protein control the lac operon binds to four repeating binding regions on the DNA. Since one dimer can be connected to one operator sequence, two dimers are connected to two operator region units, and as a result the result is a loop formation in the DNA structure. Consequently, because of the access of RNA polymerase to the promoter region, the pre-coding process of genes is hindered. If the hindering protein is in the form of a monomer, the operator displays a weak interaction with half of the sequence. In the dimer form there is a stable binding. For this reason, many procedures in the cell occur by working together and making a union of molecules. Since the loop shape of DNA stabilizes the structure, it prevents the RNA polymerase from being connected to the promoter region. In order to eliminate the blockage on the lac operon, the mutual relationship must be prevented by stimulatory molecules, such as lactose.

There is metabolic information in cells that measure and control the physiological condition. The sequences on the regulatory region of the lactose operator and the data concerning the physiological condition of the lactose and glucose metabolisms are analyzed in the cell which perceives the presence and the amount of glucose through the changes in the system that transports the glucose into the cell. The molecule that announces the presence of glucose in E.coli is cyclic-AMP and concentration of this molecule in the cell is inversely proportional to glucose. The level of this signal affects both the coding and regulation of genomic information. The protein that transports glucose into the cell contains a phosphate group; as it transports glucose into the cell, this carrier protein phosphorylates the glucose molecule thereby loosing its phosphate group. As a result, the proportion phosphorylated transport protein and those without phosphate provides information about the glucose level in the cell. The phosphorylated form of the carrier protein activates the adenosine cyclase enzyme. Through this enzyme, ATP is converted into cyclic-AMP. The cyclic-AMP level increases in the cell. Consequently, the situation that concerns the increasing concentration of the phosphorylated transfer protein and the cyclic-AMP is interpreted as non-existence of glucose in the cell. The CRP protein that binds to regulatory region of the lactose can only bind to this region in the presence of cyclic-AMP. The cyclic-AMP-CRP complex which is tied to the promoter region of the lactose gene speeds up the transcription of the lactose operon. Transcription rarely happens when there is no lactose. This is because the lactose repressor protein lacI, hinders the RNA polymerase reaching the lactose promoter region by binding to the operator of regulating region. The cell can sense the existence of lactose in a circuitous manner. Low levels of coded Permease enzyme on the lacY region transfer some lactose into the cell. The coded beta galactosidase on the lac Z region alters them into a sugar called allolactose. The allolactose is bound to the lacI repressor protein and changes its conformation. The allolactose –lacI repressor complex can not bind to the operator region. The promoter region, called LacP, of Lactose operon is set free for transcription. In fact, every one of these molecular interactions is an incident of information being transferred. All these incidents demonstrate that an algorithm (If there is no glucose and only lactose exists, then transcribe the lacZYA enzyme) that is able to distinguish the difference between two sugars exists in bacteria cells and that it functions perfectly.

In short, the signal transfer in lactose operon occurs with the activation of chemical molecules that represent the experimental data pertaining to the physiological environment of the cells. For example, the levels of cyclic-AMP, allolactose and protein phosphorylation indicate the existence of glucose and lactose. The regulating network system, on the other hand, combines many aspects of cell activity (transport, enzymology, energy metabolism) in order to make the transcription decision. Briefly, it is impossible to show that arranging the order of the genome in any cell occurs independently from physiological or biochemical processes.

The principle of “using combinations in the arrangement of specific binding regions” is commonly used in metabolic signal networks that control cell physiology and the differentiation of cell (morphogenesis) that are oriented towards tissue formation. Such an interaction takes place on these network paths between proteins and DNA sequences to ensure that the cell is allowed to process molecular information and to calculate whether it will transcribe a specific genetic sequence. The common binding regions on DNA have vital roles in the coordinated control of various genetic loci, and it is then that the decoding of genes in a harmonious (symphonic) manner becomes possible. Various combinations of these regions are also used in making more complex decisions. As an example, protein-binding regions that are involved in the lowest level of genomic indicators have a role in decoding genes. The proteins that bind to these DNA sequences can become active when they form a group that has an interaction with more than one protein molecule. For instance, each one of the lacO and CRP regions on the lactose operon shows a palindromic sequence structure (the DNA sequence remains the same when the sequence is read from either end). Similarly, the lacP region has two lower regions that are appropriate for the binding of RNA polymerase and are separated from each other by a 16–17 base pair. In all living beings, the proteins and DNA sequences interact with each other. For example, the LacI repressor, which is in charge of controlling the lactose operon,has separate regions for not only binding the DNA region, but also for creating protein-protein binding as well as the binding of allolactose stimulator. The unique combinations of this region on the genome sequence result in a unique protein synthesis.

The genetic engineering procedures in cells

Some of the genetic engineering procedures that take place in the cells are as follows: Recombination systems (mutual material exchange) that are observed in homologous chromosomes (the chromosome pair derived from each parent), recombination specific to a particular region; separation of DNA sequences specific to those regions (fusion of gene pieces, VDJ recombination of genes as appointed in the immune system); the existence of systems that combine end points in non-homologous chromosomes (the binding of broken DNA parts, the formation of new genetic fusion, the formation of sequences that are open to hyper mutations); DNA transposons (DNA sequences that can insert themselves into different DNA sequences or can copy themselves there and leave a copy); the RNA sector that can control the transcription and signals that are responsible for the maturing transcription; the signal sequences that cause the rearrangement of neighboring DNA sequences (such as amplification, deletion, and inversion); and finally, controlling the transcription with micro RNAs.

None of the above phenomena which cause in-cell changes are random. Each of the genetic engineering functions is planned in a way that makes specific changes and arrangements. In the processes of insertion, i.e. when a specific amount of DNA is added to a different region of the genome, or deletion, i.e. when a specific amount of DNA is severed, there should be arranging, cutting and coding sequences that will bind the cut part to its new place in an appropriate way. On the genome, special regions that are suitable to mutation are created in order to produce variety and to respond to adaptation. When all these molecular engineering functions are thoroughly analyzed, it can be seen that even the point mutations, which up until now were thought to have happened by chance, are not coincidence; rather, they occur through the divinely designed genetic engineering functions. Most of the mutations that are thought to occur by chance in the cell have been removed by the repair systems and fault correction functions in the cell. Thus, the changeability and variety in DNA sequences are shaped by the power and will of God the Almighty according to a planned, programmed genetic schedule.

The R&D department of the genome

Depending on the stimulation received, God-given genetic engineering functions are arranged in the cells and a decision is made about which parts of the genome should be changed. Some of the changes inside the cell appear on a large scale. Inside the genome, different and far removed regions can be rearranged. The changes are related to one another and are in no way disconnected. One mechanism can produce more than one change. The reconstruction of changes in some organisms is a part of the normal life cycle. In the Cornelius protozoan, the embryonic genome is regularly decomposed to a thousand slices. Then, through processing and rearranging in the cells, a functional genome with a distinct system structure is created.

While the genome is reshaped, there is the production of new different sequences rather than the sequences that they regulate and which have the code for the continuity of existing phenotype features. The organization of the genome along the system base emerges with the functions of the genetic molecules, such as cut-paste-rearrange. For example, in immune system cells, there is a planned disposition to mutation and the specific antibodies are rearranged to recognize an infinite number of different antigens. The life cycles of lymphocytes demonstrates both the control of the DNA rearrangement improvements and the specificity of mutations. It is estimated that the new sequences which do not change the existing structure operate like a research center for the genome.

The God-given genetic engineering systems imposed in the cells, when analyzed from the perspective of the population, are molecular mechanisms that carry out basic changes to ensure adaptation. The duty of reconstructing the genome during adaptation has been assigned to the divine genetic engineering functions imposed in the cell. The divine genetic engineering tools and mechanisms, which are placed in the cell with active nucleic acid elements that carry information, change the genome in parallel to the changes in both the inner and outer environment; this change occurs not only on one point of the genome, but rather on every point of genome. The functions of the DNA elements, which allow for the exchange of genetic information (both horizontally and vertically, in species and between species, between types and classes), are arranged by domestic cell signal transfer and data process networks. The signal network systems that are in charge of rearranging and controlling in-cell procedures not only control when the genome is rearranged, at the same time it decides where these rearrangements take place inside the genome. The selection of the target is planned, it is not random. For instance, R1 and R2 retrotransposons which are established in the DNA region that codes 28S ribosomal RNA have specific recognition regions and the information of endonuclease cutting DNA region on specific points that it had settled down. Eukaryotic cells have more complex decision making systems. The cells continuously create responses in response to DNA damage, cell physiology and outer-cell reproduction factors. One of the critical questions and answers is whether the damage will be repaired or whether programmed death will take place. If the cell avoids giving an answer, then genetic indecisiveness appears and abnormal cell reproduction, i.e., cancer, begins. From this perspective, cancer is a result of pathology in the signal and information process in the cell. The changes in gene expression without any changes in the DNA sequence (epigenetic) as well as the divine genetic engineering functions are clear proof demonstrating that every single action in the cell occurs with a certain aim that is based on knowledge and calculations.

Hamza Aydin holds a PhD in biology.

References

• Shapiro J. A.(2001). “Genome Formatting for Computation and Function: Genome Organization and Reorganization in Evolution: Formatting for Computation and Function.” Presented at the “Contextualizing the Genome” symposium, Ghent University, Belgium, November 25–28, 2001 (Ann. N.Y. Acad. Sci., in press).
• –. (2005). “A 21st century view of evolution: genome system architecture, repetitive DNA, and natural genetic engineering.” Gene 345 (2005) pp. 91–100.
• Shapiro J. A. and Sternberg R V (2005). “Why repetitive DNA is essential to genome function.” Biol. Rev. (2005), 80, pp. 1–24. Cambridge Philosophical Society. DOI: 10.1017/S1464793104006657.

We live in a world full of technological devices, instruments and machines. Even if we buy them from good retailers, our cars we use to commute, or our CD-players and nowadays the mp3-players we use to listen to music one day break down, and eventually we change them. Can you imagine a TV which never gets old and can be used forever? The answer is obviously no. But we human beings have a miraculous system that always repairs itself-a system called DNA Repair. The proteins which are produced using DNA as a template, are also used to repair DNA when necessary. Before going into details of DNA repair, let us look at what DNA is, what DNA damage is, and how it occurs.

DNA (deoxyribonucleic acid) is one of four major macromolecules (the others being carbohydrates, lipids, and proteins) that constitute living things. DNA mainly contains genetic information encoded by a combination of four different DNA building blocks, nucleotides, to produce proteins. These proteins in turn play a role in cellular reactions. Genetic material is faithfully copied and passed on from generation to generation, perpetuating the characteristics of the parent and providing children with the information necessary for existence. Our sex, most of our personalities, as well as physical traits (eye color, hair color) are dependent on DNA as a part of the biological order established in our body. Moreover, even aging is a result of the shortening of the packed DNA (chromosome) through time. DNA is crucial for our body, but having such a unique molecule can come at a cost. In particular, cancer and many other disorders are thought to be caused by a lack of proper DNA-handling in cells, due to a defect in DNA repair.

DNA is a fairly stable molecule made up of two strands. Along each individual there are covalent bonds which hold sugar and phosphates together, and the two complementary strands of DNA are bound by hydrogen bonds. But, are these bonds strong enough? Are they unbreakable? To be able to function properly is DNA ever in need of maintenance? Like everything in this world, DNA too can be fragile in extreme conditions (Figure 1). Physical or chemical agents that might cause changes in DNA are commonly known as DNA-damaging agents or mutagens. Mutagens can be either endogenous (like free radicals which are produced from normal metabolic byproducts) or exogenous (like UV radiation or some toxic food chemicals). In addition, DNA can be damaged when synthesizing itself before cell division. These changes may be caused by enzymatic errors or mis-incorporation of nucleotides. Studies have shown that DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day. While this constitutes only 0.000165% of the human genome’s approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell’s ability to carry out its function and appreciably increase the likelihood of cancer formation.

Although there are many ways that DNA can be damaged, we are equipped with DNA repair mechanisms that can reverse the process. As soon as damage occurs to the DNA, it is detected by sensor proteins. These proteins scan the DNA all the time for any bulges or breaks. Once damage is identified the proteins tag it and DNA repair is initiated. A second precaution against damage is provided by a process called DNA Damage Checkpoint (Figure 1). Once this has been activated, cell division is delayed or comes to a halt in order to prevent the change from being passed on to any new cells.

Damage can occur on a single strand or on both strands. Depending on where or how the damage has been introduced, we have different repair systems for each type of DNA damage (Figure 2). In figure 2 we can see the difference between the original, undamaged DNA and the damaged DNA. The DNA repair systems responsible for repairing different defects are also shown in the figure to give a better idea of different DNA repair systems. Of particular interest is the fact that there are more than 150 genes that have been identified to date as being related to DNA repair. When we consider the number of possible defects that can threaten the DNA, this number is surprisingly low in comparison to the total number of genes (~ 30,000 as estimated by the Consortium of the Human Genome Project). Related to that, research in recent years has started to show that the genes which are important for one particular type of DNA repair are in fact required for different repair systems too. When we think about the enormous number of defects introduced into the DNA as opposed to the very few number of proteins involved in DNA repair (as compared to the whole genome), we can easily appreciate the perfection of the system. To give an idea of how DNA is repaired a nucleotide excision repair is shown in figure 3. At the top of the figure, UV exposure causes damage to the DNA. After that, DNA repair is initiated and recognizes the damage. The proteins (represented by circles in different colors) which are responsible for the repair act one after another to bring the DNA back to its original, intact shape.

If damage in DNA is not repaired at all, then the cells with the damaged DNA are either eliminated via a process called apoptosis or mutation occurs. The term mutation refers to permanent changes in the DNA. Although most people assume mutations are harmful, they can be silent or even beneficial depending on the region of DNA in which they occur. In the worst case, when they are deleterious, they can cause many genetically related disorders as well as cancers (Table 1). In this table, we can see different disorders which are caused by lack of appropriate repair systems.

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and might also result in premature aging. Biologically, aging is an irreversible state in which the cell no longer divides, and is a protective response to the shortening of the DNA ends (telomeres). The telomeres are long regions of repetitive DNA that undergo partial degradation each time a cell is divided. Aging in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell is required by the organism, thus serving as a “last resort” mechanism to prevent a cell with damaged DNA from dividing inappropriately. Since inappropriate division might lead to cancer, the induction of aging and apoptosis is considered to be part of a strategy to protect against cancer.

On the other hand, there is an interesting example for researchers where we see a proficiency of DNA repair activity in an organism called deinococcus radiodurans, the most radiation-resistant organism known to date. Specifically, it exhibits a remarkable resistance to radioactivity (which in turn causes double strand breaks on DNA) most likely due to enhanced DNA repair.

In this article we have tried to answer the question of what DNA repair is, how it is regulated in the cells and what the results of a deficiency in DNA repair are. Studying wonders like the DNA of our biological system is a means of contemplation that leads us to deep reflection on the intricacies of the universe. But one question remains unanswered, how has DNA learned to repair itself?

Hasan Altinbasak is a researcher at the National Institutes of Health.

References

• Lodish H, Berk A., Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Biology of the Cell, p. 963. WH Freeman: New York, NY. 5th ed.
• A physical map of the human genome. The International Human Genome Mapping Consortium. Nature 409, 934–941 (15 February 2001)
• http://www.riken.jp/engn/r-world/info/release/tress/2005/050609_2/index.html
• Wood RD, Mitchell M, Lindahl T. Human DNA repair genes, 2005. Mutat Res. 2005 Sep 4;577(1-2):275-83.
• Tom Strachan, Andrew Read. 2003. Human Molecular Genetics. John Wiley & Sons Inc.
• http://bbrp.llnl.gov/repair/html/overview.html
• http://biology-pages.info

We inherit our hereditary characteristics from our parents. The basic unit responsible for inheritance in our body is the gene. More technically, a gene is a hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome and determines a particular characteristic in an organism. Genes are like words on the long string of DNA. The description of the fundamental process of synthesizing proteins from the information on genes is called the “Central Dogma.” According to this dogma, DNA is used to synthesize RNA, and in turn, RNA is used to synthesize proteins. Hence, this dogma dictates the link between genes and proteins. Proteins are actually a translated and three-dimensional version of the linear information stored in genes.

The Structure of DNA

DNA (Deoxyribonucleic acid) is our repository of genetic information. Although there are organisms such as RNA viruses that possess RNA (ribonucleic acid) as their genetic material, virtually all other living organisms inherit their genes through DNA. Hence, DNA is vital for the existence and perpetuation of life on Earth.

In a simple comparison, DNA can be likened to a sequence of letters where each letter is a single nucleotide, and the alphabet has only four letters: A, T, C and G. Although this alphabet is extremely small compared to those used in human communication today, we are still capable of capturing the vast size of human DNA with this analogy: Our DNA is composed of a sequence of nearly 3 billion (3,000,000,000) of these letters. What this means is that, if you were to type out your genetic code, you would have a 5,000-volume encyclopedia, with each volume containing 400 pages, and each page having 1,500 letters! But then, how do we even fit this formidable size of information in every single cell of our body? The answer lies in the astonishing folding, packaging and wrapping steps DNA goes through upon synthesis. Positioning nucleotides side by side, each DNA molecule would take up about 6 feet (~2 meters) of space. However, after all the packaging steps, DNA becomes compact enough to fit in not only a cell, but also in the microscopic nucleus of each cell.

Genes and the Human Genome Project

Unfortunate for our alphabet analogy above, the 3 billion nucleotides in DNA do not contain any spaces to let us know where each word begins and ends. The Human Genome Project accomplished the task of unraveling what these 3 billion letters are (each one is one of A,T,C and G) and this was a major achievement of humanity. However, it was not until then that we realized the real challenge DNA posed us: Where were the genes in DNA? In other words, how would we understand the words and sentences in this 3-billion string of letters? Apart from efforts to discover the DNA sequences of other organisms, it is not unfair to say that the interest and workforce once focused on the Human Genome Project has now almost completely shifted to this latter “real” challenge of discovering the genes in DNA.

How we wish life could be that easy! Just as completing the human DNA sequence made us realize that we did not know where the genes are, discovering some genes allowed us to understand that we would still be missing a major part of the picture even if we knew exactly where each gene was. Do we not frequently encounter instances in everyday life where one word means different things depending on context? So, is there any good reason to think that genes on our chromosomes will be any less complex? Unfortunately not. Quite to the contrary, the sense is growing that genes are actually far more complex and intricate than we originally thought. For one thing, a single gene may not cause an immediate effect, but may interact with a network of other genes to produce the final effect. Diseases that are caused by individual genes are actually very few, a famous example being cystic fibrosis. But diseases that are affected by the interaction of many genes are far more numerous and prevalent, for example, breast cancer, Alzheimer’s disease, Type 1 diabetes mellitus, multiple sclerosis and obesity.

This latter group of diseases is appropriately called “complex diseases.” Efforts are under way to decipher the intricate genetic and protein networks responsible for such diseases; however, there are so many (known and also unknown) variables that biologists have already called for help. Research problems such as complex diseases that require the interaction of biologists, mathematicians, computer scientists and statisticians alike have led to the advent of the currently very popular field of “Systems Biology.” Viewing the cell as a large factory, this field aims to understand all molecular networks and interactions that make up the very sophisticated machinery in living systems. After deciphering how cells operate flawlessly as a complex system, humans will be better able to discover causes of diseases, and will also be in a much better position to manipulate cells to cure diseases.

The idea of manipulating cells and cell components such as genes and proteins has actually led to “Synthetic Biology,” which is, in essence, the engineering approach to Systems Biology. Synthetic biologists try to engineer gene and protein networks in the cellular machinery to program cells for synthesizing custom-tailored molecules. This can be in the form of redesigning or producing mass amounts of existing molecules, or synthesizing nonexistent molecules that have medical or other potential uses. The overall significance of the field can be well understood by the following quote from one of the pioneers of the field, UC Berkeley professor Jay Keasling: “(Synthetic biology is) doing for biology what electrical engineering did for physics and what chemical engineering has done for chemistry.”

One example of synthetic biology comes from Jay Keasling’s lab. In collaboration with the Gates Foundation and OneWorld Health, the first nonprofit pharmaceutical in the US, Dr. Keasling’s lab is engineering a new metabolic pathway in E.coli to produce the precursor to artemisinin, currently the most effective treatment for malaria. The prospects include a drastic drop in cost, from dollars to dimes. Moreover, success in redesigning a metabolic pathway in bacteria holds great promise for reproducibility for other similar pathways important for the pharmaceutical, cosmetics and food industries.

Genomics vs. proteomics

Molecular biologists, today, are inundated with neologies ending with the suffix “-ome” and “-omics.” The consequence is that the expression “–omics” craze has found its place in the everyday language of these scientists. Basically, the suffix “-om-” refers to a totality of some sort. All the genes considered as a whole in an organism’s cell are called the “genome, and similarly all the proteins this genome can synthesize are referred to as the “proteome.” “Genomics” and “proteomics” refer to the study of the relevant “-ome,” as opposed to studying genes and proteins one by one.

Even though there exist so many –omics words in the literature these days, genomics and proteomics remain the most popular and useful ones. Proteomics can be thought of as the natural successor to genomics because it is fundamentally the next level of complexity after genomics. While scientists explore gene networks and their interactions in genomics, proteomics involves the study of all the proteins and their interactions in the cellular machinery of an organism. Unfortunately, the next level of complexity does not mean “linearly more complex” in this case; studying networks of three-dimensional molecules is an immensely more daunting task than studying those of one-dimensional DNA sequences. However, luckily for us, scientists are up to this challenge. Yet again, we observe a shift in focus in the scientific community from genomics to proteomics.

The main motivation for this shift can be roughly understood with an analogy from marketing or another one from military warfare. In the former, if you want a better marketing strategy for your product, you should target end-users first and foremost. Understanding behavioral patterns and preferences of end-users is much more important than understanding likes of your vendors, because eventually it is the end-user who will determine the demand for your product. In the latter analogy, we think of an army of soldiers who receive orders from a general commander; however, these orders can later be modified or completely annulled by orders from other commanders still in the hierarchical order. If you think about how reliable and informative knowing the orders that each soldier has received from the general commander is going to be, you will understand how useful it will be to have information on genes without supplementary information on proteins. Gene products, either RNAs or proteins, may undergo some steps called “post-translational modification” that are not completely understood, and worse yet may not be completely deterministic (implying random factors).

So, with the help of the analogies mentioned above, we can reason that the shift in focus of the scientific community from genomics to proteomics is mainly due to the fact that biological functions are carried out, not by DNA or genes, but by proteins and (although much less frequently than by proteins) by RNA molecules. For medical and other practical purposes, it is more important to acquire information on the proteome rather than the genome. This, of course, is not to suggest underestimating the importance of the genome. The genome preserves its significance as the origin and source of genetic information. It is just not as beneficial to think about the genome without looking at the final product, that is the proteome.

Conclusion

The completion of the rough draft of the Human Genome Project in 2000 marked the end of the Genetic Era and paved the way to the Genomic Era. The breakthroughs that have taken place since this cornerstone event have been breathtaking, awe-inspiring and maybe even hard to catch up with. The Genomic Era had given birth to different fields in a span of few years, and the biological scientific community has had to shift its focus from genomics to proteomics even without having sorted out the puzzles of the genome. The advent of the “-omics craze” was probably a by-product of this shift because suddenly each sub-field of molecular biology had to adapt a holistic approach in its explorations. Investigating a single entity, whether it be a gene or a protein or another molecule, quickly became stigmatized as “obsolete.”

This transition to a holistic approach has resulted in the interaction of biologists with scientists from quantitative fields such as mathematics, statistics and computer science. These interactions gave rise to truly interdisciplinary research fields such as systems biology, synthetic biology and computational biology. More and more scientists today believe that competence in the future will rely on incorporating expertise from these different fields. With each new discovery, realizing the level of complexity and the intricacy in the design of our body leaves us in true awe. Moreover, these discoveries only make it easier for us to grasp how little we know about the miraculous design of biological systems. On the other hand, this awareness makes us even more motivated to delve into scientific efforts because understanding the science behind creation takes us directly to the understanding of our Creator.

Jason Newfoundland is a PhD candidate in Bioinformatics at University of Michigan.

Notes

1. http://www.answers.com/topic/gene?cat=technology
2. This amazing process is demonstrated in this link: http://www.dnai.org/text/mediashowcase/index2.html?id=556
3. Synthetic Biology: Change on the Horizon, Karsten Temme, http://no.oneslistening.com/277
4. A glossary for –omics words exists at http://www.genomicglossaries.com/content/omes.asp

The second leading cause of death in the United States, after heart diseases, is cancer, claiming around half a million lives every year.(1) People today are concerned more than ever about cancer and its terrible consequences. However, in the light of recent scientific findings, a very different picture can be seen: In an environment with increasing carcinogens, it is actually surprising to find most populations are cancer-free. This is because our bodies are equipped with systems to prevent cancer formation.

Cancer research over the last two decades has shown that cancer is a disease of the genome.(2) Changes in the DNA, called mutations, disrupt the regular cellular networks that control a state of delicate balance. People are continuously exposed to varying amounts of chemicals that have been shown to cause mutations in the genome which may lead to cancer formation. Exposure to harmful chemicals can occur due to being in an environment where these agents are present in the food, air or water, and also due to our own metabolism which may produce these chemicals. It has been estimated that exposure to environmental chemical carcinogens may contribute significantly to the formation of the majority of human cancers.(3)

Even though some of the mutations caused by these agents hit cancer-critical genes, cancer does not immediately develop. Furthermore, cancer is mostly seen in old age, when many mutations have accumulated in the genome. The reason why we are protected from developing cancer, even though our DNA is under numerous types of attacks everyday, is that our cells are equipped with several lines of defense against cancer formation. These built-in defenses include DNA damage repair systems, external and internal controls of cell division rate, and the programmed death of cells. All of these defenses have been given to our cells in order to protect us from getting cancer. If we were not to have these defenses, cancer would be a daily occurrence for every one.

It is possible to say that a cell’s first defense against cancer is similar to the regular maintenance of a car. One has to replace the brake pads, change the oil, etc., so that the aging of the parts will not cause failure that may lead to an accident. Similarly, chemical carcinogens from environmental pollution, ultraviolet rays from the sun, radiation from various sources, etc. all cause multiple types of damage in the DNA molecule. Therefore, our cells and genome need maintenance as well. This function is carried out by groups of proteins called DNA repair complexes. DNA repair mechanisms have been designed to correct the DNA damage before it can lead to inheritable mutations.(4)

If the DNA damage repair systems are intact, most of the damages to the genome are dealt with before they can cause problems. We observe the extent of attacks that can damage the DNA on our genome in many types of cancer where the DNA repair mechanisms are known to have been inactivated. In these cancer cells, mutations accumulate at a very fast rate, leading to more aberrant behavior. Also, individuals with defective DNA repair systems are more susceptible to developing various types of cancer.(4,5) Therefore, the first line of defense given to our cells against cancer is the ability to check and correct the integrity of our genome.

Every cell type in our body has been designed to proliferate at a certain rate that is suitable for the function of those cells. For example, neurons or muscle cells almost never divide after reaching adulthood, whereas the epithelial cells lining the interior of the intestines or under the skin divide at a fast rate continuously throughout our lives. The rate of division of a cell is mainly controlled by extra-cellular cues, i.e. a normal cell doesn’t grow or divide unless it receives growth and proliferation signals from neighboring cells.

There is a safe rate at which a cell must divide – just as a car needs to be driven at a safe speed. The requirement of cells for external stimuli in order to grow and divide is like the car’s need for someone to step on the gas pedal in order to accelerate. Normal cells cannot grow without control as neighboring cells produce growth signals when they are necessary and stop producing them in a regulated manner. A good example of the control of cell proliferation rate is seen in the wound healing process. When there is a cut in the skin, the cells adjacent to the wound are stimulated to divide rapidly by signals given from the injured cells; they divide and close the wound as soon as possible. However, when there are no wounds, there is no signal to divide and the skin cells only divide at a very slow rate, just enough to replace dying cells; this is a much slower process than wound healing. Cancer cells, on the other hand, are known to produce their own growth signals and proliferate abnormally fast and in an uncontrolled manner.(6) Therefore, the environmental control of cell division is an important barrier against cancer formation.

Cancer cells cannot divide uncontrollably unless they are independent of the external stimuli to divide. However, cancer cells can produce their own growth and proliferation signals, so they are free from external constraints. But even then, all is not yet lost. This situation of uncontrolled and rapid cellular proliferation is like a car in which the accelerator has become jammed– the car accelerates continuously and an accident is impending. In this situation the way to prevent too much speed is to step on the brake of the car. Similarly, in a cell, there are a set of genes called tumor-suppressor genes, which are responsible for stopping cell division upon excessive growth stimuli.(7) These genes act like brakes in cell division and prevent further progression into a malignant state. In many cancers,(8) it has been shown that these genes have been inactivated. If the brakes of the car are functional, you can safely bring your car to a stop and fix the problem that caused the accelerator to jam. Similarly, if a cell starts to divide too rapidly, it can stop dividing and repair the damage that caused the uncontrolled growth. Therefore, tumor suppressor genes represent a third line of defense.

If all the previous safety valves fail, there is one more defense to cancer. A situation in which a cell with harmful mutations promotes its own proliferation and cannot abort the division process is similar to one where the accelerator of the car is jammed and the brakes don’t work. In this case, in order to prevent greater damage, one can choose to hit a wall or a tree to stop the car– this will total the car, but will prevent further damage to others. Similarly, if a cell begins to grow uncontrollably and can’t slow down its rate of division, a process called apoptosis, or programmed cell death is initiated. In apoptosis, the cellular DNA and cellular compartments, like lysozomes, Endoplasmic Reticulum, and Golgi are degraded, and the cell shrinks in size. In the end, the cell dies and is absorbed by neighboring normal tissue. Therefore, the programmed death of an aberrantly behaving cell is another way that the body is protected from cancer. As expected, in cancer cells defects in this last line of defense are observed as well.(9)

These four mechanisms, i.e. DNA repair, external/ internal cell division suppression, and programmed cell death, are only the ones that we are aware of at this time. In addition to these, there are multiple levels of other redundant safety checks. All these safety features work without our knowledge or will. Findings from cancer research show that the design of cells was carried out so intelligently that even the carcinogenic environment which we produce today was accounted for within the genes of the very first human being.

Notes

1. Cancer Statistics 2006. 2006, American Cancer Society.

2. Vogelstein, B. and K.W. Kinzler, “The multistep nature of cancer.” Trends Genet, 1993. 9(4): p. 138-41.

3. Wogan, G.N., et al., “Environmental and chemical carcinogenesis.” Semin Cancer Biol, 2004. 14(6): p. 473-86.

4. Dixon, K. and E. Kopras, “Genetic alterations and DNA repair in human carcinogenesis.” Semin Cancer Biol, 2004. 14(6): p. 441-8.

5. Jiricny, J., “The multifaceted mismatch-repair system.” Nat Rev Mol Cell Biol, 2006. 7(5): p. 335-46.

6. Brattain, M.G., et al., “Growth factor balance and tumor progression.” Curr Opin Oncol, 1994. 6(1): p. 77-81.

7. Hanahan, D. and R.A. Weinberg, “The hallmarks of cancer.” Cell, 2000. 100(1): p. 57-70.

8. Coleman, W.B. and G.J. Tsongalis, “Molecular mechanisms of human carcinogenesis.” Exs, 2006(96): p. 321-49.

9. Dlamini, Z., Z. Mbita, and T. Ledwaba, “Can targeting apoptosis resolve the cancer saga?” Future Oncol, 2005. 1(3): p. 339-49.

With the full extent of its use not being understood at the time of its establishment, the project emerged mainly with the pharmaceutical mission to predict, detect, treat, and cure diseases that were caused by genetic anomalies by identifying the genetic information in the human organism.

The desire for such a project was something akin to, or even beyond, the desire to climb Mount Everest, for it aimed to find out something that was unknown at the time. In such fields of biology as cell biology, immunology, and neurology the specialists need genetic information from human organism. The genetic information that an individual organism inherits from its parents can open a door to answer the questions of how an individual develops, how long an individual will live, or how the various species on Earth have lived over many generations.

New developments followed one upon another with the emergence of the Human Genome Project. When the famous Scottish sheep, Dolly, was cloned in 1997, it still seemed to be theoretically impossible to clone a human being. American scientists cloned an ape named Tetra which shared 98 per cent of the same genetic information as human beings. Soon after this, the scientists began to suggest that that all that remained to be cloned was humans.

Dr. Richard Nicholson, the editor of the Bulletin of Medical Ethics, noted that there is no danger in cloning humans, as long as the techniques of doing so are kept under control. If a dictator, however, were to get hold of this information, they would be able to produce an army of genotypically identical soldiers.

The most exciting scientific study of recent years of the Genome Project is that it is trying to develop a complete gene map of an individual organism. According to scientists, a human body has between thirty thousand and fifty thousand genes. All genetic features identifying an individual are found in the gene sequences of the DNA molecules. Eye color, character traits, IQ, and all the illnesses a person may possibly develop are all hidden in the genes. The genome carries all the hereditary features that determine all of life’s diversity, determining whether an organism is human or another species, or ape; all living things have their own genomes. The human genome, which is the full complement of genetic material, and which resembles large tablets recording the history of ancient civilizations, is distributed among 23 sets of chromosomes. It is comprised of approximately three billion letters and is the biological record of our destiny.

Ethical, Legal, and Social Issues

In H. G. Wells’ classic novel The Island of Dr. Moreau (1896), Dr. Moreau conducts hybrid experiments on animals that result in twisted masses of flesh, half-man, half-animal. When the European Patent Office allowed the Australian company Amrad to obtain new embryos by combining human and animal cells, this led to a revival of genetic fears, more than a hundred years after the story of Dr Moreau was published. Not surprisingly, this event alarmed several civilian organizations, including Greenpeace. In a press statement made in Hamburg, Greenpeace drew attention to the fact that we might face “dangerous creatures” in the future that would be created from such techniques. Probably one of the most disturbing facts was that the patent did not disclose how these creatures were to be used. Greenpeace voiced opposition to this for the following reason: “A patent grants its owner the exclusive control over his/her invention. Therefore, patents on life fundamentally change our perception and understanding of living nature and our relationship towards it. Living organisms, which have been ‘created’ by industry and which can be patented cannot have a value of their own, since they are only considered an invention of human beings. Thus they can be exploited without any ethical concerns.”

According to the patent, the embryonic stem cells derived from humans, mice, birds, sheep, pigs, cattle, goats, or fish could be used. The patent covers a “method of producing a non-human chimeric animal” by mixing human and animal embryonic cells: human stem cells are integrated into animal embryos. As a result, the created chimeras are non-human, but they may contain human organs, body parts, nerve cells, and even human genetic codes.

Experts state that the system of producing chimeras is completely different from that of cloning and they drew attention to the risks involved. For example, a virus like the one that caused mad-cow disease could easily pass from one species to another.

The Media Joins the Issue

Thanks to the great interest people have shown in the future of genetic studies, we frequently come across news reports that deal with the topic. However, we would like to note that titles like “the homosexuality gene has been found” or “genetic solution to talkativeness discovered” infuriate genetic scientists. Dr Arnold Munnich says that media aims to raise interest by misinforming the public with subjects like “obesity gene” or “laziness gene”; they merely oversimplify the issue. Dr Munnich emphasizes that a gene means nothing by itself.

The Danger of Abuse

The researches who have worked toward improving gene technology have performed some good for humanity; this is without a doubt. However, there is the risk of abuse. The discoveries in this field may be worth a great deal financially; when we add the rivalry between companies and countries, it seems highly likely that legal bans and ethical rules will be ignored. Some people even object to all kinds of genetic research, not only their abuse. They say that the abuse of seemingly useful genetic technology practices in the future is possible, as has happened in other fields of technology; nuclear researches and laser technology also used to be innocent studies at the very beginning. But we cannot object to the use of electricity just because it is also used for executing people with electric chairs.

Governments and international organizations are quite sensitive to ensure that gene technology will only be used for the good of humanity. There are several international organizations interested in the ethical dimension of the issue. There are certain rules and regulations that establish the fundamental principles that will prevent the abuse of genetic studies, and protect the biodiversity and ecological balance. It is forbidden to carry out research on human cloning and altering human embryos. In the past, dictators like Adolf Hitler attempted to abuse gene technology in this respect. The ruthless Dr Joseph Mengele tried to clone his Fuhrer from the epitel cells he took from him.

Will Confidentiality be Respected?

Another concern brought about by new diagnosis methods and tests is that the principle of patient confidentiality, which has existed for centuries like a secret agreement between doctors and their patients, has begun to be debated, even violated. We usually talk about such “confidentiality” when the information is likely to be harmful for the patient if publicized. From this perspective, the results obtained by genetic tests can be evaluated as such. It is one of the duties of doctors to maintain patient confidentiality. On the other hand, if the relevant data is also likely to harm society, the hospital staff, and those around the patient, then the doctor can face a dilemma.

Some of the possible problems that may be faced due to the mapping of human genome will be that employers could be provided with forehand knowledge about the potential genetic diseases of applicants; they may know whether the person to be employed will be a future financial burden to the company if they carry such genetic risks as cancer or Parkinson’s. In this way new standards of employment will be developed. Even though systematical public surveys do not indicate any significant dangers at hand, it would be nearly impossible to stop rumors. Several people may be denied insurance if they have the genes for a fatal disease. Another may be dismissed from their job for the same reason. In the USA, it is illegal in 39 states to issue insurance policies according to genetic test results, and it is also illegal in 15 states to expel employees according to these. However, employers and insurance agents take advantage of the gaps in relevant laws and they secretly make use of genetic tests. According to research carried out in 1999, 30% of medium-sized or small businesses use such tests to promote and dismiss their employees.

Psychologically, it does not seem likely that people would consent to their status being determined by genetic tests. Would you really like to face your genetic disadvantages? A survey made with cooperation of Time magazine and CNN revealed that half of the participants did not want to know.

The Fate of an Unborn Baby

Deciphering the book of life unfortunately brings along ethical problems. The discovery of our genetic codes can also lead to other humans controlling the future of the human race. The critical question is “Can scientists produce human beings with the desired physical and mental qualities?” If so, genomic science may enable biologists to prepare a list of spare parts, parents may “order” a baby, and as altering our children or ourselves gets easier, we may be less tolerant against those who have not been altered. Lori Andrews of Kent University wonders if we were to be informed of mental defects, obesity, shortness or other undesired characteristics beforehand, whether the parents of those babies would still allow them to be born into a society that scorns such qualities. Even now, it is not uncommon to see some doctors and nurses criticize the parents of babies who are born with pre-detectable defects. If we assume that all parents have “ordered” babies, God knows what kind of a world we will have.

What Should the Aim of Such Practices Be?

Genetic studies should aim to prevent or treat illnesses, not to “enhance” genes. The opportunities offered by genetics should not be a mass elimination medium used by employers or a mechanism of spotting potential criminals in the hands of oppressive regimes. The Almighty One Who has been running the order of our universe so perfectly has granted us some keys to its mysteries. Why should we not do our best and use them for the good of humanity?

References

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