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.

We know our bodies to be more than just an assembly of organs and each organ is much more than an assembly of specialized cells. So what makes life so precious and awe-inspiring to those who care to stop and think? Most of the time of our life-span, be it hours, days, weeks, months or many years, we are totally oblivious of the immense complexities which operate within us.

Just as fascinating as the why and how of early embryo development (gastrulation) is the phenomenon of cell death. Even as cells are proliferating and differentiating in the various stages of gastrulation, many individual cells must be sacrificed for the benefit of the whole. Do not be alarmed at this expression – thousands and millions of our cells die and some may be replaced many times during the average adult life. The most common example is that of our skin cells. Up to 90% of household dust consists of dead skin cells. Old blood cells in circulation are constantly removed by the liver and replaced by new cells manufactured in our bone marrow. But there are more subtle forms of cell death of which we were, until recently, quite ignorant.

All cells in multi-cellular organisms are capable of committing suicide in response to signals from other cells. Sometimes the absence of a given signal heralds the onset of programmed cell death. Two distinct forms of cell death have been identified by researchers in the field [1]. These are known as 1) necrotic cell death and 2) apoptotic cell death. The first is quite a common and well-observed phenomenon which occurs when cells die from severe and sudden injury. Also known as accidental death, examples of such events leading to necrosis are ischaemia, sustained hypothermia, and physical or chemical trauma. In necrosis the mitochondria (required for producing energy in cells) undergo changes which are visible as changes in their shape. The plasma membrane is often the major site of damage and homeostatic control of the cell’s environment is lost. As a result the cell first swells then ruptures, spilling its contents into the surrounding tissue space. This provokes an inflammatory response namely the attraction of patrolling white blood cells which clear away the debris by engulfing and ingesting it. Thus the process of repair can begin. Apoptosis, on the other hand, exhibits a completely different set of morphological features and the process is much more refined. It is not observed during accidental cell death but appears to be an integrated part of the normal process of tissue regulation. Let us take a closer look at this fascinating phenomenon and see what it involves:

The main characteristic associated with apoptosis is the distinct set of morphological events which take place (see Figure 1). Whereas necrotic cell death results in cell lysis and a consequent inflammatory response, apoptotic cell death is very much the opposite where the size of the cell decreases (rather than increasing through swelling) and there is no spillage of cell material.

Figure 1:

a) Normal cell with sparse cytoplasm and heterogeneous chromatin;

b) The start of Apoptosis: sonic loss of cell volume, cytoplasmic organelles are tightly packed and the chromatin condenses;

c) ‘Zeiosis’ i.e. ruffling of plasma membrane;

d) Chromatin collapses into crescents along the nuclear envelope, very condensed in appearance;

e) Nucleus collapses into central black hole;

f) Fragmentation of the collapsed nuclear material into small spheres;

g) Formation of apoptotic bodies.

It has been proposed that the sixth step of apoptosis makes it a foolproof method of disposing of cells since once destroyed, DNA (which is the vital blueprint of cells) cannot be re-assembled. This ensures irreversible removal of defective / harmful DNA material so that none of them can resist apoptotic death once it has been initiated.

Why Die? – the functional roles of Apoptosis:

Apoptotic cell death can occur in a number of physiologically acceptable situations. Some well- observed, but still poorly understood, examples are cited below:

a) tissue re-modeling during embryonic development As mentioned earlier, whilst new cells are being generated a significant number of early cells die to make room for others to form the sophisticated multi-cellular organisms that we are: e.g. cells which form the ‘webs’ between the fingers and toes in the early stages of development, thus leaving them free to move.

b) migration of cells into abnormal locations. Tumour cells are prime examples where such migrated cells can cause damage to other cell-functions and are thus, best removed promptly and discreetly.

c) cells which are no longer functional. To refer to a non-human example, the metamorphosis of tadpole to adult frog includes, amongst other changes, the loss of the tail.

d) removal of cells produced in excess – developing sympathetic neurones are always produced in higher numbers than required. These then compete for nerve-growth-factor released by their target cells. In this way the number of neurones innervating target cells is matched to the number of target cells available through competition for the growth-factor.

e) specialized cells need to be selected for specific functions. In the thymocytes of developing embryos, antigen receptors on T-cells are selected for, i.e. T-cell lymphocytes expressing the correct type of receptors are retained whilst those whose receptors have too high or too low affinity for antigens die through apoptosis. If the receptor affinity is too high it will attack the cells of the body, those with insufficient affinity are of no use and thus, meet the same end. As a result the body accumulates a repertoire of lymphocytes which are useful in the fight against foreign matter yet do not harm the self.

Examples a), b) and c) are in opposition to the ‘Theory of Evolution’ i.e. there is no outright competition for survival. The concept of ‘survival of the fittest’ does not apply

Take another striking example: the flatworm, Caernabhditis elegans (C.elegans), has a short lifespan and a simple body plan. It has been well studied and of its developmental stages leading to the adult, the following has been noted: of the 1,090 somatic cells (i.e. all cells except the sex cells) 131 die during development, each with morphological features resembling apoptosis. Each of the 131 cells dies at a precise time and the timing of their death is absolutely reproducible i.e. every one of these 131 cells dies at a time identical in every C.elegans. This is defined as being true programmed cell death by apoptosis. Once again there is no competition between the cells to outlive their counterparts.

Because of its simple body plan it has been possible to map the development of C.elegans in such detail. No doubt, if it were possible for us to do the same for other complex organisms, including ourselves, we would discover greater precision in timing and developmental control. How else do single fertilized eggs become the perfectly-formed animals or humans that roam the wide world?

Unable to grapple with the idea that all living cells in multi-cellular organisms are capable of, and are apparently programmed to sacrifice themselves for the sake of the whole community i.e. the organism itself, Martin Raff [2] has put forward his ‘extreme view’. He claims that cell-suicide occurs by default. In other words, cells are programmed to die and only live if they receive appropriate signals from other cells. As yet, there is insufficient evidence for this ‘extreme view’, a term used by Raff himself to describe his theory. Consequently, his research is aimed at finding evidence of ‘never-lasting life’. This implies that living cells sustain each other and therefore, also implies that organisms are self-sustaining entities. It also incorporates the denial of the need for any external life-giving source. Inevitably, the whole concept is blatantly opposed to the belief in the existence of a Creator and Sustainer of the Worlds.

How did these cells acquire the intelligence behind altruism i.e. this selfless death for the benefit of the whole? One is compelled to ask whether individual cells really comprehend the greatness of their death in relation to the survival of the whole organism? Do they have the far-sighted knowledge which is necessary for such noble suicide or are they just obeying orders from a much greater source of wisdom and knowledge i.e. the All-Knowing Creator of the whole organism and the self-sacrificing cells? Whether it be caused by the presence or absence of sophisticated chemical signals ‘natural programmed cell-death’ is truly an event to marvel at. Because of the absence of inflammation, large-scale ‘normal’ cell death causes no disturbance in the body of the organism and is one of the reasons why it received less attention from researchers than necrosis. Whatever the cellular mechanisms of apoptosis, the ability to die without any fuss is a manifestation of complete submission (meaning of the Arabic word islam) to their final destiny.

Even as you read this, extensive research into apoptosis is being carried out. Without cell death or even death of any living thing, life on earth would be uncontrolled, lacking in organization and endless! The ultimate catastrophe, indeed. Greater understanding of the how and why of cell death may enable us to intervene in preventing or initiating the process. Researchers are most intent on preventing cell death. It seems that their final dream would be to defy death itself. Future revelations of details about the how and why of cell death can only add to our awe before the All-Knowing, the All-Wise, the Creator of all realms within and beyond our comprehension.

References 

1 KERR, J. F. R., WYLLIE, A. H. & CURRIE, A.R. (1972) British Journal of Cancer 26, pp.239-57.

2 RAFF, M. C., (1992) Nature 356, pp.397-9 FURTHER READING:

a) COHEN, J. J. (1993) Immunology Today 14, pp.126-30.

b) COLLINS, M. K. L. & RIVAS, A. L. (1993) TIBS 78, pp. 307-8

c) BUTTKE, T. M. & SANDSTROM, P. A. (1994) Immunology Today 15, (1), pp.7-103.

d) HOCKENBERRY, (1993) Cell 75, pp.241-51.