There are many ongoing studies into fasting, a practice prescribed across many religions. Increasingly, there is evidence to support that intermittent fasting is beneficial to human health.

The opposite of fasting – overeating – has been revealed to be a major culprit in many illnesses, including cancer, obesity, and heart disease. For many years, the medical consensus was that fasting, i.e. prolonged hunger, too, could have deleterious effects on the human body. From kidney failure to loss of muscle, fasting was believed to be harmful – thus calling into question the benefits of this widespread religious commandment.

People of faith – including Muslims – have long believed that God wouldn’t recommend a practice that was harmful to the body. The hardships and troubles that accompany a religious practice are not too extreme for people aware of their servitude to God: they regard their trials as a testament of their faith. Part of that faith is the certainty that God wouldn’t recommend a harmful or unbearable practice.

In this article, we will share with you two unknown benefits of fasting that have been recently discovered.

Regenerating stem cells

There is a substantial body of evidence showing that staying hungry during certain periods of the day heals the body’s metabolism, hastens loss of fat, decreases oxidative stress,* and improves the functions of the tissues that make up various organs including the liver, the intestines, and the brain. The first of the two new discoveries about the underlying processes, however, provides a missing piece of the puzzle by helping us understand the incredible changes hunger triggers in stem cells.

Researchers at MIT, Duke University School of Medicine, and Whitehead Institute for Biomedical Research in Cambridge published an article recently on stem cells, indicating that part of stem cell’s mystery could lie in the oxidation (burning) of fat in the mitochondria [1]. Omer H. Yilmaz and his fellow researchers found that a 24-hour fast hastens fat breakdown in intestinal stem and special progenitor cells of rats.

To run the study, Yilmaz and colleagues let the mice go hungry for 24 hours to study the state of their stem cells. They found that the functions of intestinal stem cells increased, and fat metabolism quickened, in both young and aged mice, even during early periods of hunger. They saw that the body’s tapping into fat for its energy needs maintained the health and strength of the intestinal stem cells. Moreover, they noticed that if the aged mice did not fast, they started to lose their ability to break down and use fats for energy expenditure.

The researchers obtained more interesting results as the studies progressed. It was found that a single period of hunger for 24 hours boosted renewal of intestinal cells – and the stem cell functions increased even more significantly in aged mice. Another interesting finding was that mice with damaged intestines that were fasted recovered faster than those that were fed.

“My lab is really interested in understanding how diet, in general, can be used to improve tissue function,” Yilmaz said. “One of the tissue types I study is the intestine. In my lab we study the intestine because it’s one of the largest organs in the body. It’s also a tissue that experiences rapid cellular turnover.” [2]

The intestine is lined by a single layer of cells, Yilmaz explains, that turns over every 5 to 7 days. The workhorses of the intestinal lining and this cellular turnover are intestinal stem cells. These cells must retain a high level of function or cellular health in order to replenish the intestinal epithelium on a regular basis. Intestinal stem cells are particularly important in terms of repairing intestinal damage caused by gut infections and chemotherapy, for example.

The single layer of epithelial cells needs to be renewed every 5-7 days: the aids and enzymes secreted in the intestine for digestive and absorptive activities damage cells despite the protective mucus layer, and some other cells already burst and die as they empty their secretions. Moreover, some medications, particularly chemotherapy, cause the destruction and breakdown of the epithelial cell layer. However, fast-multiplying stem cells replenish the epithelial cells. Stem cells are very active and young and have the ability to divide and multiply continuously.

Dr. Yilmaz also says:

“As we age, stem cells in the intestine as well as in many other tissues of the body, including in the blood and nervous systems, become less functional. We believe that reduced adult stem cell function contributes to some of the decline of function associated with old age. My lab is very interested in studying low-calorie interventions to delay this decline. As a field, we’ve known for over 100 years that low-calorie states such as fasting or caloric restriction can have positive effects on tissue health and aging. We’ve seen evidence that fasting during times of intestinal infections that lead to diarrhea may promote healing of the intestinal lining, for example.” [2]

This quote emphasizes the importance of the issue. Yilmaz adds that despite all this knowledge, the cellular mechanisms of this renewal have not been discovered, and he and his team are working to find out how fasting and hunger enable this recovery.

Stem cells become happy in fat!

The researchers discovered through the experiments that the stem cell function could be brought about in hungry mice by the burning (oxidation) of fatty acids in intestinal cells. When they stopped the fat metabolism through genetic engineering, they noticed that the benefits of fasting on intestinal stem cells were negligent.

In the present dietary conditions, we obtain nearly 60-70% of our energy from carbohydrates or sugar, 20% from fats and 10% from amino acids. Yet an interesting finding revealed by Dr. Yılmaz and his research team is that we essentially obtain much greater energy from using fats once we fast. According to their experiments on mice, during fasting, the intestinal stem cells in both young and aged mice switch from carbohydrates to fats as the primary source of energy, and this shift enables improvement in stem cell functions.

It is not yet known what underlies the fat metabolism that boosts stem cell functions in response to fasting, but it is observed that stem cells work better when they burn fat. The ability to metabolize fats efficiently decreases with age.

It is likely that this hastened metabolism – encouraged by certain diets, like the keto diet, where the amount of fat ingested is raised to 70% and carbohydrate intake is limited to 5% – helps with epileptic seizures and similar neurological disorders: the ketone bodies generated during metabolism of fats are used as energy sources by the brain.

According to Dr. Yilmaz, if fasting can improve the functions of intestinal stem cells through metabolism of fats, the key is the mitochondria, the powerhouses of the cell responsible for this function. Fat metabolism, or the immediate breaking down or “burning” of the fat entering the cell, is carried out in the mitochondria. Disrupted energy generation associated with aging and decreasing mitochondria can be a reason for the brain’s susceptibility to age-related illnesses. Positive developments in brain functions can therefore be viewed in connection with the correlation between fasting and the oxidation of fatty acids.

Cleaning by fasting

Just like the spring cleaning in our homes, our cells need a thorough cleaning to function properly. Wrongly folded protein particles, remains of damaged organelles, broken molecular pieces, and aged cells that can no longer divide should be disposed out of our cellular structure. Fasting perfectly performs the task of cleaning these wastes and clearing the area in the cell.

“Everything has zakat (a means of cleaning), and the zakat of the body is fasting.” (Ibn-i Majah, Siyam: 44)
“Fasting is a protective shield.” (Bukhari, Sawm: 2)

What is autophagy?

Autophagy is the compound of two ancient Greek words: auto (self) and phagos (eating). What is meant by “self-eating,” is the breaking down and recycling of protein waste and old, impaired molecules by intracellular digestive organelles called lysosomes. In this way, proteins or cellular organelles are digested and taken out of circulation. We can liken autophagy to garbage collection.

Japanese researcher Yoshinori Ohsumi’s study, which brought him the 2016 Nobel Prize for Medicine, found that the autophagy that occurs inside the cell due to fasting or starvation plays an important role in preventing ageing, infections, and tumors. If autophagy breaks down, many illnesses may be triggered, including cancer. Conversely, if autophagy activity is regular, tumors may be suppressed – depending on the stage of development and type of tumor. Cancer research has long focused on channeling these autophagic activities. Restriction of food intake through fasting shows promise: it may protect normal cells while triggering autophagy and thus increasing the effect of cancer treatments. Autophagy might offer solutions or treatment options for other illnesses, too, including inflammatory diseases [3], neurodegeneration [4], metabolic and cardiovascular diseases [5], obesity [6], and metabolic disorders.

Preclinical studies have shown that dietary restrictions by fasting contribute to the increase of a person’s lifespan and slow the development of age-related diseases such as cancer and neurodegenerative and cardiovascular diseases [7].

* Oxidative stress: The damage caused as a result of excessive proliferation of free oxygen radicals released from foods that spike blood sugar (with high glycemic index) as metabolic waste. A good example of oxidative stress is the browning of certain foodstuff such as apples, bananas, etc. sometime after they are peeled.

References

1. Yilmaz, Omer H. et al. 2018. “Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging.” Cell Stem Cell, Vol. 22, Issue 5, May 3, pp. 769–778.
2. Paige Brown Jarreau. 2018. “Eating (Or rather, Fasting) Our Way to Rejuvenated Stem Cells?” in Life and Tech @ LifeOmic. June 7. A Medium Corporation.
3. Cadwell K. 2016. “Crosstalk between autophagy and inflammatory signaling pathways: balancing defence and homeostasis.” Nat Rev Immunol.16 (11): 661–75.
4. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A et al. 2017. “Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities.” Neuron. 93 (5):1015–34.
5. Bravo-San Pedro JM, Kroemer G, Galluzzi L. 2017. “Autophagy and Mitophagy in Cardiovascular Disease.” Circ Res. 120((11)):1812–24.
6. Lavallard VJ, Meijer AJ, Codogno P, Gual P. 2012: “Autophagy, signaling and obesity.” Pharmacol Res. 66 (6):513–25.
7. O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. 2017. “When less may be more: calorie restriction and response to cancer therapy.” BMC Med. 15(1):106.

MicroRNAs as tiny regulators with big roles

Tiny RNAs, known as microRNAs, have been shown to regulate many components of the body’s cellular machinery. They are called microRNAs because they are only 22 nucleotides in size (compared to the 2200 nucleotide-long messenger RNA). Amazingly, these small non-coding RNAs can turn off the translation of their target genes. They act as control switches by targeting the 3′ untranslated regions of messenger RNAs (mRNA) for translational repression or cleavage, thus resulting in a reduction of protein levels. Because each microRNAs can regulate hundreds of messenger RNAs, there are probably few cellular processes not affected by microRNAs. For instance, microRNAs have recently emerged as playing important roles in a variety of cellular processes, such as heart development, stem cells, insulin secretion, and cholesterol synthesis. MicroRNAs were first discovered in worms more than 20 years ago. For many years, scientists thought that DNA was transcribed to RNA, and then translated to protein. Those proteins are major regulators in the cell. Now, they appreciate that there are more levels of control and a number of non-coding RNAs that regulate the level of cellular components. About one thousand microRNA genes have been discovered in the human genome. This makes the microRNAs one of the most abundant classes of regulatory genes. As a result of the discovery of this new and major level of regulation in the cell, Dr. Andrew Z. Fire and Dr. Craig C. Mello were awarded the 2006 Nobel Prize in Physiology or Medicine.

MicroRNA biogenesis

Unlike other RNAs, the production of microRNAs is quite different. As depicted in figure 1, the generation and activity of microRNAs requires special microprocessors, known as RNA polymerase II, Drosha, Exportin, Dicer, and RISC complex. RNA polymerase II transcribes (reads the microRNA DNA code) primary microRNA transcripts; then the Drosha process transforms primary microRNA into precursor microRNA in the nucleus. For activity and further processing, precursor microRNA are exported into cytoplasm by Exportin. In the cytoplasm, Dicer cuts precursor microRNA and generates mature 22 nucleotide long microRNA. Then, mature microRNA are incorporated into the RNA inducible silencing complex (RISC) where they target messenger RNAs (mRNA), either for degradation or translational repression. Even though there are extensive studies on microRNAs, it is still mostly unknown how microRNAs target specificity is determined and how they target messenger RNAs for mRNA degradation or translational repression. For a functional microRNA in the cell, it is amazing that a series of microprocessors should take place. They recognize different microRNAs as substrates and do their job as they are supposed to. It seems that the existence and regulation of microRNA processing abilities cannot be by mere chance.

MicroRNAs as therapeutics

MicroRNAs are considered “fine tuners” of cellular processes because of their subtle effects on their targets. However, because microRNAs can target a number of genes and genetic pathways, the study of microRNAs and their regulation and role in diseases is highly promising in terms of developing new therapeutic approaches. Treatments by targeting microRNAs using microRNA inhibitors (antisense RNA nucleotides) are under intense study and several of them have been shown to be effective in animal models. A MicroRNA known as miR-122, for instance, has been shown to regulate cholesterol levels. Scientists targeted this liver-specific microRNA by using a microRNA inhibitor and they found that the downregulation of miR-122 resulted in a 40% decrease in cholesterol levels in the blood.

MicroRNAs in cancer therapy

With the discovery of new and better tools to detect and manipulate microRNA levels in cell cultures and tissues, researchers are now attempting to identify the specific features of each microRNA and their role in cancer and other devastating diseases. There are some microRNAs that are highly correlated with cancer formation. Cancer is cellular anarchy characterized by a proliferation of cells without control. A group of miRNAs known as the miR-17-92 family have been found to increase, and their higher levels result in cancer formation as found in some lymphomas and solid tumors. It is believed that better understanding and use of microRNAs or microRNA inhibitors could enable doctors to treat diseases like cancer. In the near future, microRNA studies are also expected to provide early detection of progressive diseases, better markers for cancer initiation, and cancer specific drug selections.

MicroRNAs as cancer drug boosters

The most straightforward application of microRNA research has been cancer chemotherapies. The potential of use of microRNA applications to increase the effectiveness of current cancer drugs seems highly likely. Companies and universities are looking for microRNA partners to increase the effects of drugs like Taxol, which is currently used in chemotherapy. Taxol, for example, currently works for about 30% of lung cancer patients. But, if we can find a microRNA partner with that drug to make it 40%, it will mean saving thousands of lives. This is a hopeful sign for the future of cancer treatment. On the other hand, it is known that in the case of any chemotherapy, there are unwanted side effects. Although use of higher dose of drug will kill more tumors, the side effects of this drug will cause other issues. Discovery of partners like microRNAs that boost the effectiveness of cancer drugs or decrease side effects can help to treat more patients or help them overcome unwanted side effects.

Taking microRNAs to the heart of the matter

Heart diseases represent the primary cause of death in developed countries. Recent studies have identified microRNAs associated with heart diseases, including cardiac hypertrophy, heart failure (inability of the heart to pump sufficient blood to the organism), and myocardial infarction (the death of the cardiac muscle resulting from interruption of the blood supply). Mir-1 expression levels, for example, are low in human heart disease and it is known to regulate Hand2, a protein required for the growth of heart muscle cells. The levels of another microRNA, called miR-21, have consistently increased through cardiac stress and have been shown to regulate cardiac growth as well. Importantly, miR-133 is believed to repress cardiac hypertrophy, thus the use of synthetic miR-133 molecules is possible as a therapeutic for patients with pathological hypertrophy. However, more studies to understand heart-associated miRNAs are needed in order to have clinical trials for the treatment of heart diseases.

Figure 2. MicroRNAs in the heart. Recent studies have identified microRNAs that are associated with heart diseases, including arrhythmic heartbeat (Arrhythmias), cardiac hypertrophy (enlarged heart), septation defect, and cardiac muscle overgrowth (myocyte hyperplasia).

Micromanaging insulin secretion

MicroRNAs are also associated with the onset of diabetes. Diabetes affects about 23.6 million people in the United States. It can lead to serious health issues and even early death. Diabetes is marked by high levels of blood glucose (also called blood sugar). Complications of the disease are due to defects in insulin production and insulin action. Insulin is among the major regulators of sugar levels in the blood. The human genome contains a number of microRNA genes, whose functions are only beginning to come to light. One such microRNA, miR-375, is already implicated in the secretion of insulin from pancreatic cells, thus it represents a novel pharmacological target for the treatment of diabetes.

The mentioned cases above are examples of the tiny RNAs which regulate cellular processes. The loss of the control in such a small component of the cellular machinery can lead to serious problems, like cancer. To use a metaphor, the regular and healthy government of a state does not allow for the presence of multiple governors. Similarly, regulatory tiny RNAs require a controller who knows how the human body works at the macro and micro levels. This forces us to consider that whomever is controlling the human body must be all sustaining and all knowing. With each new scientific breakthrough, the wisdom of creation becomes more and more apparent. The field of miRNAs is a young research area. New discoveries about microRNAs have brought us new hopes for novel therapies to human diseases. However, future discoveries are required before these therapies can be used in a clinical setting.

Resources

• Qur’an: The Family of Imran 191 and The Cow 255.
• Caldas & Brenton. “Sizing up microRNAs as cancer genes”. Nature, 2005.
• Scott M. Hammond. “MicroRNA therapeutics: a new niche for antisense nucleic acids” Trends in Molecular Medicine, 2006.
• Rooij et al. “Toward MicroRNA–Based Therapeutics for Heart Disease” Circulation Research, 2008.
• National Diabetes Statistics, 2007. Retrived from http://diabetes.niddk.nih.gov/DM/PUBS/statistics/
• ScienceDaily. Not ‘Junk DNA’ After All: Tiny RNAs Play Big Role Controlling Genes. 2007.
• Callis & Wang. Taking microRNAs to heart. Trends in Molecular Medicine. 2008.
• Poy et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature,2004.
• Average mRNA length: B. Lewin, Genes 5, Table 2-2. Oxford University Press.
• MicroRNA biogenesis figure: http://content.nejm.org/content/vol359/issue25/images/large/14f1.jpeg

Ibn ‘Arabi was such a determined one. He is a strong milestone in the history of mysticism. His heritage goes beyond Muslim identity and encompasses a following from diverse traditions. In this issue, Brenda Pletcher explores Ibn ‘Arabi’s mystical legacy as a firm foundation for interreligious dialogue. For Pletcher, Ibn ‘Arabi’s philosophy of “diversity within unity,” as symbolized by his vision of a Universal Tree surrounded by four mystical birds, reveals dialogues “of life, of study, of prayer, and of spirituality, all of which, if followed in an atmosphere of mutuality, will have the potential to facilitate people toward the dialogue of action—an action bringing forth a vision of justice for all.”

Just as these great messengers enrich our spirits, so do fruits enrich our bodies.. We love their taste and smell, and are aware of their health benefits. However, a great majority of us do not consume fruits when we should – we are not even aware of when we should. “When To Eat Fruits” explains reasons why fruits should not be consumed right after a meal, and why we should eat them at least an hour before the main course, or two hours after. It is a very useful read on the right consumption of one of the most important components of our daily diet, which we wrongfully substitute with industrially processed juices.

Like eating well, recycling has become integral to our daily lives. We collect the food remains in our kitchen and the leaves in our backyard. We separate paper from plastic, all in the hopes of making our planet’s body healthier.. But were you aware that recycling has always been a part of our body’s survival mechanisms? Abdullah Acar says there are recycling centers in our cells which “have the duty to help with the digestion of cellular trash (i.e. damaged cellular organelles, misfolded proteins, toxic loads) so that energy can be generated and raw material obtained for the construction of new cellular units.” Named autophagy (i.e. self-eating), this recycling phenomenon “is primarily activated or enhanced via fasting or food deprivation.”

The Fountain is bringing scholars from different disciplines and traditions together in Istanbul on November 5-7 for a three-day workshop to have “Conversations on Life, Knowledge, and Belief.” The purpose is to pave the way for The Fountain to be a platform of thoughtful discussions on cross-cultural dialogue, scientific thought, faith, and philosophy. We will keep you posted about the event.

With all of its faculties, a human being can be thought of as an index of the whole universe. Therefore, we witness correlations between the processes taking place in the human body and in the universe. Accordingly, the world we live in has a correspondence to human biology. For example, the cyclical processes in the environment (water cycle, carbon cycle, etc.) ensure the continuous recycling of the same matter, hence the cleanliness of the habitat for all. Similarly, the human body includes mechanisms to cleanse itself from harmful and unnecessary materials.

Prior to the development of such an understanding, the prevailing attitude encouraged consuming natural resources and using the environment as a “trash can.” Even today, we live in a world that promotes excessive consumption of daily goods leading to accumulation of incredible amounts of trash. For example, in developed Western societies, an average family discards more than one ton of trash every year, which is mostly paper, packaging material, and kitchen waste.

Nevertheless, as we realize the importance of the recycling systems in nature and the multi-faceted harms of trash accumulation on the environment, recycling of conventional and technological waste is encouraged by collecting plastics, glass, paper, and tins. On a larger scale, recycling centers have been developed to minimize the damage to the environment and to meet the need for raw materials.

The recycling process consists of three main steps as depicted by the famous three-arrows symbol representing 1) the collection of materials, 2) the remanufacture of new materials from the collected ones, and 3) reselling or reusing as new products. Thus, recycling centers not only contribute to the economy, but also serve as clearance sites to maintain the harmony of the environment.

Cellular recycling through “fasting”

Similar to recycling centers at the macro level, there are recycling centers in the cellular level too. These centers have the duty to help with the digestion of cellular trash (i.e. damaged cellular organelles, misfolded proteins, toxic load) so that energy can be generated and raw material obtained for the construction of new cellular units. This recycling phenomenon was simply named as autophagy (i.e. self-eating) by cell biologists. What is interesting, though, is that autophagy is primarily activated or enhanced via fasting or food deprivation.

How autophagy works

Autophagy is a process that occurs when astarving cell starts to form double membrane containers through an orchestration of several proteins. These containers are called autophagic vesicles or autophagosomes ¹. Their main role is to target and collect cellular trash. Then, they start to fuse with lysosomes, the digestion centers of the cells, to degrade the trash into building blocks—amino acids. The amino acids can then be used both for the construction of new proteins needed by the cell and in the production of ATP, which is a source of energy for the cell.

The whole process corresponds to micro-scale representation of a real world recycling concept: collection, re-manufacture and resell/reuse. Through autophagy, a cell recycles its own material and obtains energy ².

Fasting: An emerging trend

With the discovery of mechanisms initiating autophagy and its involvement in various diseases such as cancer, neurodegenerative disorders, auto-immune diseases etc., autophagy has gained a unique significance that is progressively increasing ³. After the year 2000, the number of publications on autophagy-related research began to increase exponentially. Moreover, due to the increased conviction about the link between fasting and autophagy, fasting started to become a real trend in modern civilizations. Let’s examine a few of the important recent findings that reveal the relationship between autophagy and fasting.

In a study involving mice, the response to fasting was assessed in liver cells (hepatocytes) by tracking the presence of a protein (GFP-LC3) that indicates autophagy. It was seen that the lack of food, which is the source of energy, led to the disintegration of mitochondria, which are the power plants of the cells. Subsequently, the components that made up those mitochondria were re-utilized for the building of other necessary proteins⁴. These results indicate that unnecessary mitochondria were eliminated for the sake of recycling organic materials during fasting.

Neurodegenerative diseases, such as Alzheimer’s or Parkinson, etc, are linked to the accumulation of trash in the brain cells, which is indicative of a lack of autophagy. Drugs developed for these diseases do not possess effective treatments since they are unable to penetrate into the brain cells (a concept known as the blood-brain barrier). During another study involving mice, in one track, animals were exposed to fasting, and in the other, their brain cells, (more precisely cortical neurons and Purkinje cells) were isolated and exposed to food deprivation. In both tracks, researchers observed that fasting enhanced autophagy, suggesting that fasting could be a simple, cheap, and safe therapeutic cure for prevention of neurodegenerative diseases ⁵.

In another study, this time involving a subset of kidney cells (proximal tubule cells), a lack of autophagy resulted in the accumulation of dysfunctional mitochondria and other cellular debris. As a result, the cells grew in size abnormally (hypertrophy), decreasing the functionality of the kidney. This suggested that autophagy was part of the continuous maintenance of proximal tubule cells and that inducing autophagy in the kidney may provide a novel therapeutic approach to minimize acute kidney injury ⁶.

As a final example, one more study revealing the association between autophagy and the immune response should be mentioned. It was found that the number of autophagic vesicles (chambers) in the macrophages, a subset of immune cells that are the first to perceive threats to our body, increased as a response to invading bacteria. These vesicles wrapped, sequestered, and digested the bacteria eaten by macrophages ⁷. Thus, fasting has the potential to improve the fighting ability of macrophages against invading pathogens by enhancing autophagic machinery.

Taken together, the autophagy process seems to be a recycling mechanism with minor variations depending on the cell type and activation triggers. Once initiated, it leads to a) reduced accumulation of cellular trash (toxic protein aggregates); b) an improved immune response for removing bacteria (intracellular pathogens); and c) the protection of the interior of the cell (cytosol). As one of the main stimulators of autophagy, fasting or food deprivation seems to be a way for improving health.

Next time you fast, keep in mind that while you are starving, your cells are feasting for your health. Just as the natural world is structured to continually cleanse and renew the earth, fasting seems to trigger similar processes inside the human body. While individuals may choose to fast for spiritual cleansing, their physical bodies experience a cleansing as well.

Abdullah Acar is freelance writer in the US with a special interest in biology.

References

1. Mizushima, N., et al., Autophagy fights disease through cellular self-digestion. Nature, 2008. 451(7182): p. 1069-75.
2. Mizushima, N. and M. Komatsu, Autophagy: renovation of cells and tissues. Cell, 2011. 147(4): p. 728-41.
3. Yang, Z. and D.J. Klionsky, Eaten alive: a history of macroautophagy. Nat Cell Biol, 2010. 12(9): p. 814-22.
4. Kim, I. and J.J. Lemasters, Mitochondrial degradation by autophagy (mitophagy) in GFP-LC3 transgenic hepatocytes during nutrient deprivation. Am J Physiol Cell Physiol, 2011. 300(2): p. C308-17.
5. Alirezaei, M., et al., Short-term fasting induces profound neuronal autophagy. Autophagy, 2010. 6(6): p. 702-10.
6. Kimura, T., et al., Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J Am Soc Nephrol, 2011. 22(5): p. 902-13.
7. Fujita, N. and T. Yoshimori, Ubiquitination-mediated autophagy against invading bacteria. Curr Opin Cell Biol, 2011. 23(4): p. 492-7.

One of the signs of anarchy in a region could be the marching of an army to get a particular situation under control and, if it is indispensible, destroy or suppress anarchists. Similarly, the first response of the body to such uncontrolled growth is the destruction of tumor cells by activating inner mechanisms that lead to cellular suicide (apoptosis). Anarchy is by definition not to accept any border and authority, causing disorder or upheaval. According to twentieth century thinker Nursi, anarchy cuts and throws away norms and laws that organize social life, one by one, thus destroying the order and leading to mischief and rebellion. In addition, anarchism does not consider the rights of any. Analogously, one by one, cancer breaks genetic rules that organizes cell proliferation and eliminates pathways that suppress tumor formation. Thus, it eradicates the order and triggers chaos and malignancy. Again, cancer works against the life of the body without considering the rights of other cells.

Another characteristic of anarchism could be the elimination of its leaders. Thus, once you get rid of the key players, anarchy may not resurface. Likewise, you can use a strategy in certain cancer types where you can specifically target cancer stem cells. As a result, cancer growth could be suspended and it may bring an opportunity to shrink tumor through chemotherapeutical approaches. One such example is the targeting of CD24, a putative cancer stem cell antigen expressed by a minority of adenocarcinoma cells. This cell-based cancer immunotherapy method uses genetically engineered cancer killing T cells, which are directed towards cancerous tissues using chimeric antigen receptors. This is similar to the taking over of trained Special Forces when anarchy becomes malicious and unceasing. Both natural and genetically engineered cancer killer T cells in our body resemble trained Special Forces that patients need to fight against cancer.

Cancer treatments

Cancer is nowadays mainly treated with chemotherapy, radiotherapy and surgery, and to some extent with immunotherapy. The many purposes of chemotherapy include relieving or preventing the suffering of the patient, prolonging the life span, and if possible, completely curing the cancer along with surgery or radiotherapy regimens. Chemotherapy mainly uses cytotoxic drugs that kill cells by attacking one of the main properties of cancer cells—rapid division. Unfortunately, since cancer cells are not the only rapidly dividing cells in the body, chemotherapeutic agents also harm healthy cells. Another fall back of chemotherapy drugs is the lack of specificity that does not provide a therapy against a specific cancer type and their efficacy vary from patient to patient. In these cases, the indispensable path is synergistic use of radiotherapy with chemotherapy.

As its name implies, radiotherapy involves the use of ionizing radiation to kill cancer. It relies on the destruction of dividing cells by introducing DNA damage, which leads to induction of cellular death through apoptosis. Radiotherapy is therapeutically useful in cancers that are localized to one part of the body. It is also useful to prevent tumor relapse after surgical removal such as in breast cancer. However, radiation, which radiotherapy depends on, is itself the potential cause of cancer and leads to various side effects.

Citizens of the body need justice

Chemotherapy or radiotherapy, which harms both healthy and cancerous cells, recalls the practice of absolute justice versus relative justice. Absolute justice requires protection of every individual while punishing the criminals. On the other hand, relative justice is the justice where the rights of one person are ignored for the betterment of the whole. Absolute justice is always the best practice if it can be properly established. However, relative justice may be sought if absolute justice is absolutely out of reach. Current chemotherapy and radiotherapy treatments are like the practice of relative justice, which harms both cancerous and healthy cells. Of course, these treatments are considered as the last resort for many cancer patients but this analogy regarding absolute justice toward cells in the body urges us to seek for cancer therapies that follow absolute justice. In other worlds, we need to practice an approach that is more specific toward cancer cells. This could be, as we mentioned above, the use of cancer immunotherapy where cytotoxic T cells are directed towards cancer cells through genetic engineering by introducing chimeric antigen receptors (CARs). CARs should be able to recognize unique or relatively specific antigens located on the surface of cancer cells to execute them.

Cancer killing T-cells: Equipped with chimeric antigen receptors

There are three main approaches in cancer immunotherapy including immunization, use of antibodies and cellular immunotherapy. Immunization by administering a cancer vaccine prepares the patient’s own immune cells to recognize tumor cells as targets to be destroyed. The use of therapeutic antibodies specific to cancer cells recruits immune cells in the patient to abolish tumors. Cellular immunotherapy, on the other hand, uses patients’ own immune cells like the natural killer cells, cytotoxic T cells and so on. Basically, those cells could be stimulated in patients with the administration of interleukins or they could be isolated from the patients’ blood and cultured in the laboratory and following expansion and in vitro training, then transfused back to the patient to fight against cancer.

Cytotoxic T cells are unique immune cells that recognize target cells via T cell receptors. Over the past decade, scientist engineered T cell receptors and developed chimeric antigen receptors that specifically recognize target antigens. This recognition lead to signaling pathways that resulted in apoptosis of tumor cell through the production of granzymes, perforins and cytokines such as IFN-γ, and TNF-α (Figure 1). There are a number of success stories using CAR+ T cells for cancer immunotherapy used in patients. Encouraging results were obtained with CARs targeting lymphoma (by targeting CD19 antigen), coleractal Cancer (by targeting CEA antigen), and melanoma (by targeting melanocyte-specific markers MART1, MELOE-1 and gp100).

Universal chimeric antigen receptors

Two recent studies published by two different groups increased the hopes in the battle with cancer. They developed novel and universal CAR technologies that combines cell based immunotherapy and use of therapeutic monoclonal antibodies. This new approach relies on the recognition of specific molecules such as FITC and Biotin by corresponding Anti-FITC and Anti-Biotin (Avidin) CARs. The decent thing about these specific molecules is that you can attach them to any antibody, ligand, or aptamer known to target specific tumor antigens (Figure 2). One of the universal chimeric antigen receptor, for instance, uses FITC, a fluorescent molecule widely used in flow cytometric assays. Since it is easy to label antibodies, this provides wide range of antibodies to target cancer cells. In addition, scientists using this approach could target more than one tumor antigen or could use another antibody that targets different antigen even if cancer relapses. Moreover, since antibodies used to activate CAR+ T cells will degrade and their bioavailability will decrease in the body by time, there will be no need to kill injected T cells with suicide mechanisms. Once FITC labeled antibodies are stopped from being given to patients, CAR+ T cells will stop attacking cells and cease-fire since their guns (CARs) cannot recognize tumors or anything nonspecific. This approach is highly encouraging and has brought with it great hopes in the treatment of cancer.

Anarchy, spirituality, and prayer therapy

Hunger, poverty, social inequality and economical issues could be asserted as the basis of anarchy within a society. However, according to Nursi, the real basis of anarchy is spiritual weakness and poverty. Similarly, the basis for cancer could possibly be the lack of appropriate spiritual diet that may eventually make a person fall spiritually and physically weak. For example, fasting is a physical and spiritual fast prescribed in monotheistic religions which increases spirituality and has been shown to be synergistically effective in chemotherapy with cancer treatments. It has been observed and scientifically recorded that patients with strong beliefs and continuous prayers and spiritual support overcome diseases much faster than those without. This raises certain questions regarding our spiritual makeup and many other dynamics involved in being sick and getting well. So, are we getting ill because some evil spirits are manipulating our biological condition by settling in the tumors and propagating cellular anarchy? Is radiation, which leads to cellular mutations, a result of spirits that are created of “scorching fire” (The Qur’an 15:27)? Is cancer a result of such manipulations and should we seek cure for it not only through biological medicine but also through spiritual healing?

Various scientifically proven causes are known to increase the likelihood of cancer, which includes, but is not limited to, smoking, viral infections, radiation, and pollutants that lead to internal genetic faults within cells. Considering the fact that there are many cases in which patients have been reported to have recovered from their illnesses by reciting prayers, then such cases are worth examining to find out whether and to what degree non-material factors are involved as causes for our illnesses. Studying these cases may offer science new opportunities to be able to remove the present obstructions and make greater advances in the medical field by perhaps developing cancer therapies that combine prayer therapy and cancer immunotherapy using genetically engineered T cells during the treatment of patients.

Ali Fethi Toprak is a PhD candidate at University of Texas Southwestern Medical Center.

References

Döğen, Şaban. 2005. “Bediüzzaman and Anarchy.” Köprü Dergisi, No 89.

Nursi, Bediüzzaman Said. Işarâtü’l-I’caz. Şahdamar Yayınları.

Chmielewski et al. 2012. “CAR’s made it to the pancreas.” OncoImmunology 1:8, 1387–1389.

Tamada et al. 2012. “Redirecting Gene-Modified T Cells toward Various Cancer Types Using Tagged Antibodies.” Clin Cancer Res.

Urbanska et al. 2012. “A universal strategy for adoptive immunotherapy of cancer through use of a novel T cell antigen receptor.” Cancer Res.

Gülen. M. Fethullah. “Cinler, Hastalıklara Sebep Olabilir mi?” Retrieved from http://tr.fgulen.com/content/view/708/3/ on 12/24/12.

Bukhari, i’tikâf 8, 11, 12; Muslim, Salam, 24; Ibn Maja, Siyam 65; Abu Dawud, Sawm 79; Adab 81; Muslim and related hadith narrated by Abu Hurayrah, Bukhari 7.582.

¹ See Yücel, Salih. 2010. Prayer and Healing in Islam, NJ: Tughra Books.

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.

They are tiny, and there are billions of them inside you. Tiny machines, one thousand times thinner than a hair strand but strong enough to carry all kinds of material within your cells. Yes, there is a complex army of tiny machines inside your body performing an amazing array of functions while you sit at home sipping your tea.

Your heart is beating. Its lifelong duty is to pump blood to tissues to deliver essential nutrients. Transportation of nutrients continues from blood vessels to cells and then into subcellular compartments. Inside of a cell, there is a need for sophisticated biomachines which are responsible for transport. Did you know that you were equipped with minuscule motors that transported cargos in your cells? Or about cellular highways where molecular cargos are transported?

There are various proteins called “motors” in the cell. They can convert chemical energy to mechanical energy to produce force and motion in the cellular highways.¹ Amazingly, molecular motors are much superior to man-made motors in terms of energetic efficiency by hydrolyzing ATP to fuel enzymatic reactions. These molecular motors include rotary motors, polymerization motors, nucleic acid motors and cytoskeletal motors.

Rotary motors

Bacterial flagellum, used for swimming, acts as a propeller and uses a rotary motor. It has been suggested that this motor is similar to Fo motor found in FoF1-ATP synthase. FoF1-ATP synthase takes part in the conversion of chemical energy in ATP to proton gradient, or vice versa. This chemical reaction involves mechanical rotation of parts of the complex.

Polymerization and nucleic acid motors

Polymerization motors take role in polymerizations and these polymerizations generate forces for repulsion (Actin or microtubule polymerization), or separation of clathrin buds from plasma membrane (Dynamin).

DNA and RNA synthesis also involves the use of molecular motors such as RNA polymerase (RNA synthesis from DNA), DNA polymerase (DNA synthesis), Helicases (separation of double stranded DNA prior to DNA or RNA synthesis), Topoisomerases (removal of supercoiling of DNA), RSC, SWI/SNF, and SMC proteins (Chromatin remodeling and chromosome condensation). Moreover, there are specific viral DNA packaging motors that pack tightly viral DNA into capsids. separation of double stranded DNA prior to DNA or RNA synthesis), Topoisomerases (removal of supercoiling of DNA), RSC, SWI/SNF, and SMC proteins (Chromatin remodeling and chromosome condensation). Moreover, there are specific viral DNA packaging motors that pack tightly viral DNA into capsids.

Cytoskeletal motors

Dyneins, kinesins and myosins denote the three major classes of molecular motor that moves along cytoskeletal structures. Myosin is among the most prominent of motor proteins that takes role in muscle contraction. Kinesin operates on microtubules (long tubes composed of dimers of the protein tubulin, arranged to form 13 parallel tracks) to move cargos inside the cells away from the nucleus (toward positive end of microtubules) and play essential roles in the formation of spindle apparatus and axonal transport. Dynein is also known to transport cargo but in the opposite direction to Kinesin, towards the cell nucleus (toward minus end of microtubules). In addition, dynein is required to beat cilia and flagella.

How molecular motors move

Myosin and kinesin are structurally similar in terms of being dimeric with two motor heads, two legs, and a common stalk. The head regions control the forward movement by binding itself to actin or microtubule filaments. Movement is facilitated by the consumption of ATP by ATPase sites. It is fascinating how these motors translate chemical energy into motion and still be different to the movement of cars. There are different proposals as to how molecular motors move, such as walking (hand-over-hand model), inchworm model, and biased diffusion model.

The-hand-over-hand model suggests that ATP binding induces a conformational change in the forward head movements and keeps fixed, thus leading to the movement of the rear head forward and vice versa. This model, which is also known as the walking model, is similar to upright walking where one foot moves forward while other stay fixed, and vice versa. On the other hand, the inchworm model suggests that only forward head movements use ATP and leads while the other head follows. Studies on the Myosin VI with shorter legs suggested a biased diffusion model. In the diffusion model, the motor moves randomly to the next binding site in a forward direction. In order to find out which mechanism used by molecular motors, scientists measured how much of the head moves following staining with a fluorescent dye. Since molecular motor movements are so small (5-10 nM), optical traps and cantilever probes (>100 μm) were not useful to watch head movements. By increasing both photostability and brightness of organic dyes, Dr. Yildiz at UC Berkeley was able to measure head movements down to 1.5nM scale.

Kinesin: A molecular motor that walks

Kinesins are among microtubule-based motors recently shown to walk like a mountain climber by swapping its two motor units (analogous to feet) in a hand-over-hand mechanism rather than an inchworm mechanism. This recent discovery sheds light on how kinesin moves its cargos such as membrane components, messenger RNA, signaling moleculers, and others along microtubules. In addition, as suggested by findings of Dr. Yildiz, kinesin demonstrates an asymmetric walking where motor heads alternate with slow and fast steps. Further studies using advanced microscopy techniques (called FIONA) which allow nano scale detection of movement down to 2nM resolution demonstrated delicately that processive kinesin motor takes about 8 nM steps (eight-billionths of a meter) for each ATP molecule consumption with alternating 16-nm and 0-nm steps. Furthermore, kinesin is attached to the microtubule while it waits for ATP between steps. Since kinesin is used for long distance cargo transport on relatively big highways of a cell, it elegantly demonstrates a processive motor that reliably travels in a coordinated manner. Of course, not all motors will be moving like kinesin.

Dynein moves through uncoordinated stepping of ring domains

Another motor protein involved in long distance cargo transport is dynein. Dynein is a staggering giant which is much bigger and complex than kinesin and myosin motors. There are about 15 types of dyneins known to take role in cilia and flagella movement and 2 cytoplasmic forms. Cytoplasmic dynein is a homodimeric AAA+ (ATPases associated with cellular activities) motor that transports toward the microtubule minus end, acting opposite to kinesin. FIONA assay demonstrated that the heads moving processively but independently. This mechanism is quite different from the hand-over-hand stepping of kinesin and myosin, for dynein’s steps are not strictly coordinated and highly variable. Most of the time, dynein heads move alternatively with variable head-to-head distance of about 5-50nM. Each head of dynein mostly does not pass each other.

Elegant design, efficiency in transportation and being part of the living system makes molecular motors in the cells superior to man-made motors. Molecular motors travel on cellular highways in the cellular microcosm in the manner of dutiful officials of a king traveling in his domain in security via the fastest modes of transportation and easily cross provincial boundaries, demonstrating more evidently that the Sovereignty of the Eternal King is limitless. Indeed, the signs of His Dominion are reflected by each and every entity from the microcosmic world to macrocosmic universe.

Note

1 Cellular highways are composed of microtubules, microfilaments and actin filaments. Myosin moves along microfilaments through interaction with actin, but dynein and kinesin move along microtubules through interaction with tubulin

References

• DeWitt MA et al. Cytoplasmic dynein moves through uncoordinated stepping of the AAA+ ring domains. Science. 2012 Jan 13;335(6065):221-5. Epub 2011 Dec 8.
• King SM. AAA domains and organization of the dynein motor unit. J Cell Sci. 2000 Jul;113 ( Pt 14):2521-6.
• Wilhelm J. Walter & Stefan Diez. A staggering giant. Nature. Vol 482. 2 February 2012.
• Molecular motors and Motor proteins. Retrieved from Wikipedia on 3/31/2012.
• Yildiz et al. Myosin V Walks Hand-Over-Hand: Single Fluorophore Imaging with 1.5-nm Localization. Science 27 June 2003:Vol. 300 no. 5628 pp. 2061-2065
• Yildiz et al. Kinesin Walks Hand-Over-Hand. Science 30 January 2004: Vol. 303 no. 5658 pp. 676-678

Hierarchy of hematopoietic stem cells

The blood system, also known as hematopoietic system, has enormous regenerative capacity to maintain functional mature blood cells that arise from highly proliferative but short-lived progenitor cells. Those progenitors in turn are generated from very rare blood stem cells called hematopoietic stem cells (HSCs). HSCs are one of the most studied stem cells in our body which has greatly shaped our thinking on the features of adult stem cells. These stem cells are kept at the bone marrow in close proximity to bone cells and other supporting cells forming the specialized home known as niche. In several aspects, a niche resembles a cellular stronghold that a queen lives in a safe and protected environment.

The interaction of stem cells with the niche is crucial as this prevents exhaustion of stem cells from uncontrolled cellular divisions and proliferation. While active progenitors account for the generation of mature blood cells, hematopoietic stem cells function as a reserved cell population. Interestingly, we observe the importance of the balance between those two cell populations in the aging process. Although the number of HSCs increases in aged animals, there is a decline in self-renewal of HSCs.

Other protective mechanisms include the low proliferation rates of HSCs in a relatively quiescent state, residing in a low oxygen environment [3], a relatively low degree of metabolism and preferential use of glycolysis as energy source, and additional protection mechanism against oxidative stress.

Low in oxygen but a good place to be!

Stem cells as the cell bank of the body are protected against internal and external insults by a number of mechanisms. Stem cell niche not only provides an environment that they can survive but also poses the lesser degree of internal and external insults. Those possible stresses on cells include, but not limited to, UV exposure, radiation, toxic chemicals, and free oxygen species that cause various damages in the cell including mutations in DNA (Fig. 3). Cells respond to those external and internal issues by various ways such as senescence (loss of stem cell activity), cell death or DNA repair. For example, blood stem cells mainly house in the bone marrow next to osteoblastic lining (blood-forming cells) and endothelial cells where they form the hypoxic (low oxygen tension) endosteal region. This hypoxic niche of HSCs provides lower levels of oxygen so that there are lower levels of free oxygen radicals that mainly arise from electrons leaking from mitochondria during oxidative phosphorylation. In addition, it has been shown that HSC express higher levels of hypoxia inducible factor-1α, a master regulator at low oxygen tension with hundreds of downstream targets regulating various aspects of metabolism including defense against oxidative stress and survival at low oxygen environment. It has also been shown that hypoxia increases self-renewal abilities of HSCs, thus keeps them healthy and functional for longer periods.

Protection from detrimental effects of reactive oxygen species (ROS)

Excess amounts of reactive oxygen species are detrimental to cells. ROS are found to cause hematopoietic stem cell defects as shown in mouse lacking FoxO and Atm genes. In those mutant mice, the hematopoietic defects could be rescued by the use of an antioxidant N-acetyl-cysteine. Anti-oxidants are one of the scavengers that diminish unwanted effects of reactive oxygen species. A number of fruits and vegetables such as beans, blueberry, strawberry, and apple are known with their high content of anti-oxidants. It is amazing to observe anti-oxidants being placed into our sustenance just as much as in some special genes (such as SOD2 and Hypoxia Inducible factor-2α) that provide additional protection for cells. Amazingly, stem cells show high levels of ROS scavenger genes.

Low metabolism provide protection for stem cells

Recent studies demonstrate that hematopoietic stem cells have lower rates metabolism as measured by lower oxygen consumption, lower ATP content and higher lactate production (an end product of cytoplasmic glycolysis) [4]. This means that stem cells produce and consume lesser energy (ATP) compared to more differentiated cells and the by-products of the energy production are kept lower. As higher energy demand brings higher rates of internal insults like production of ROS which is associated with aging and cellular damages, HSCs are granted with another protective mechanism by preferential use of glycolysis (anaerobic) instead of oxidative phosphorylation (aerobic).

Hematopoietic stem cells are quiescent

Another defense mechanism is the quiescence of stem cells which is associated with slow cell-cycle progression. Quiescence of stem cells means that they are kept at a resting, inactive state thus sustaining a self-renewing HSC compartment for life. Because when cell divides, they have to undergo thousands of chemical reactions including making a copy of the three billion letter long DNA, which puts cells at risk to get mutations. Thus, they don’t undergo division unless there is a stimulus. In addition, it has been found that HSCs divide only once every 145 days on average.

There are a number of studies indicating that there are signals in the niche that keeps HSCs in a quiescent state. Tie2/Ang-1 signaling, for instance, has been demonstrated to contribute to the maintenance of HSCs by inducing quiescence. While Ang-1 is expressed in the mesenchymal/stromal cells of niche, its receptor Tie2 is expressed at HSCs. In addition, it has been shown that Ang-1 can inhibit HSC division in culture and promote quiescence of HSCs in the bone marrow [5].

It is also reported that the cell adhesion molecules that allow physical interaction between stem cells and their niche components may participate in regulation of stem cell quiescence through a process called contact dependent inhibition of proliferation. For instance, it has been found that cell adhesion molecules such as N-cadherin, β1-integrin, and osteopontin might be involved in the regulation of cell cycle status of HSCs [6].

One advantage of quiescence of HSC comes from the lower susceptibility of slowly proliferating cells to radiation than other cells due to the expression of cell cycle inhibitors like p21 and anti-apoptotic (controlled cell death) machinery like ATM in HSCs. In addition, studies in p21 (a cell cycle inhibitor gene) knockout mice suggest that maintaining cell cycle quiescence is directly linked to self-renewal of HSCs [7].

Toxics are exported from hematopoietic stem cells

There are other issues concerning external insults against toxics and unwanted chemicals. An HSC population described as side population has been equipped with a number of transporters such as ATP Binding Cassette (ABC) transporters, P-glycoprotein (P-gp/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) on their membrane providing high efflux ability [8]. They play an important role in the excretion of drugs and endogenous compounds. Those transporters work actively when there is an entrance or excess of such chemicals thus keeping damage minimal.

HSCs are placed in such an environment that even minimum damages by internal and external insults are prevented by different defense mechanisms including residing HSCs in the hypoxic niche, expression of ROS scavenger genes, preferential use of glycolytic metabolism, quiescence nature of HSCs, and removal of toxins by ABC transporters. It is very wise to home such an important cell in a place where it can prosper with a carefully balanced rate of cell division and metabolism. Hypoxic niche seems key to the protection of hematopoietic stem cells by supporting self-renewal and preservation of hematopoietic functions both at the same time. The presence of these protective systems that are graciously placed in our cells with perfect measurements provides an elusive mechanism to ensure healthy life-long reservoir of HSCs.

Ali Fethi Toprak is a PhD candidate at Southwestern Medical Center, Texas University.

Selected References

1. Kobayashi, C.I. and T. Suda, Regulation of reactive oxygen species in stem cells and cancer stem cells. J Cell Physiol, 2012. 227(2): p. 421-30.

2. Li, L. and H. Clevers, Coexistence of quiescent and active adult stem cells in mammals. Science, 2010. 327(5965): p. 542-5.

3. Eliasson, P. and J.I. Jonsson, The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol. 222(1): p. 17-22.

4. Simsek, T., et al., The Distinct Metabolic Profile of Hematopoietic Stem Cells Reflects Their Location in a Hypoxic Niche. Cell Stem Cell, 2010. 7(3): p. 380-390.

5. Arai, F., et al., Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell, 2004. 118(2): p. 149-61.

6. Yamashita, Y.M., D.L. Jones, and M.T. Fuller, Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science, 2003. 301(5639): p. 1547-50.

7. Cheng, T., et al., Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science, 2000. 287(5459): p. 1804-8.

8. Huls, M., F.G. Russel, and R. Masereeuw, The role of ATP binding cassette transporters in tissue defense and organ regeneration. J Pharmacol Exp Ther, 2009. 328(1): p. 3-9.

9. Antioxidant Riches Found in Unexpected Foods. Retrieved from http://www.webmd.com/food-recipes/news/20040617/antioxidants-found-unexpected-foods, January 31, 2012.

While discussions on the education of creation in schools continue, generations grow up with lack of knowledge about the Creator and understanding of His Actions. The current education system in high schools and colleges are giving knowledge about the universe, nature, earth, and life but courses are not directed to understand the Actions of the Creator. How and where can people learn about their Creator? Although there are various means such as the internet, religious groups, and journals, it is not always feasible and enough to understand directly the Creator’s Actions without a good understanding of sciences. Fortunately, every science continuously mentions God with their unique language and speaks of the Creator, but we will need a point of view, windows to see beyond our sight and knowledge, just like we need a microscope to see microorganisms or a telescope to discover depths of the universe. With some attention, everyone can understand what sciences reflect from God’s Actions. That’s why we should listen to what sciences tell us in their own language.

Imagine there is a simulation program to analyze a car crash. In this program, let us say you enter different parameters such as velocity, weight, angle of hit, general structure of the car, hardness of the body, and weather information like wind velocity and its direction and so on. After you click on the OK button in this imaginary simulation program, you almost get the same results with real physical crash tests. This obviously shows us a skillful software programmer and his great knowledge in mathematics and physical events. Noticeably, nature is composed of millions and millions of parameters determining final result just like this simulation program. For instance, when you throw a stone to a lake or into water, first of all it falls down with a velocity and then you see a wave of water expanding to its surrounding from the center affected by that velocity. The velocity of this stone at a certain time and place and wave formation on the surface of water can be explained with some physical laws described with mathematical equations. Whoever put these rules for the physical events also created the universe in a perfect mathematical order. From these and the knowledge we get from computer sciences, physics, and mathematics, we can open windows to understand the ruler of the universe as Glorious Creator.

We are at the time of great advancements in gene technology and huge increase in knowledge about molecular biology; even individual structures of biological molecules are known and many more discovered about cellular mechanisms. The more we learn, the more we face complexity and organization in the tiniest compartments of cell. Cell is no longer a small room filled with a gel-like structure in our minds, it is a massive factory that contains all required machinery and it is automatic, well balanced, and continuously renewed. Things are in constant motion; uptake follows release of substances and signal from outside results in a response produced inside. With increase in understanding of how living things are working and necessity to answer how these things originated caused discussions in scientific research. Some scientists like to talk only at scientific platforms or on so-called testable scientific subjects, but this does not change the reality. We wonder about the beginning and we wish to live forever. We are finite but dream of infinity. How can we think of eternal life if we were a product of something that is not eternal?

Imagine there is a high-tech, but small self-working factory producing highways and trucks to carry items, fuel engines for the energy that can be used in many different processes and containing solar energy collectors. There are great photocopy machines for the production of a new factory, feedback systems to control and repair any problems as well. Without any concern, control of all these events and thousands of machines, engines, highways in such a small sized factory without any problem involves a perfect engineer, scientist, architect, and chemist. Similarly, believe it or not, the cell is an excellent composition of around one million molecules, thousands of machines, and energy producing engines. There are highways, trucks, feedback systems and more in an arranged and fine control in such a small size. Mitochondria, for instance, is one of the most essential cellular organelle and produces ATP molecules as carrier of energy obtained from organic molecules for energy requiring cellular processes. In addition, cellular requirements vary by time and vesicles carry required molecules as cargo on molecular motors using microtubule pathways to different places. Those and many other examples we learn from biological sciences point to the Glorious Creator of the Earth.

When you consider a cell coming into existence by causes other than the hands of a Creator with numerous levels of regulation, coordination of subcellular compartments like organelles, information storage in DNA, and use of this information required for their specific function, it means molecules come together under the effect of natural causes and form an artistic cellular structure in a wise-manner. Actually, this reminds us of a very famous experiment by Stanley Miller to make amino acids, the building blocks of proteins, to demonstrate that life on earth has originated by natural causes and chance. Miller, in his experiment, took molecules which were supposed to represent the major components of the early Earth’s atmosphere and put them into a closed system. He used methane (CH4), ammonia (NH3), hydrogen (H2), and water (H2O) in his experiment and ran a continuous electric current to stimulate lightning storms and to drive these unfavorable reactions. He found that three amino acids have been synthesized in these conditions. Later, it was found that this composition was different from the early Earth’s atmosphere and arguments raised to his experiment due to continuous energy input not possible in nature. However, this was exciting at that time and some used headlines like “Miller created life.” On the other hand, what Miller had managed to synthesize was only a few inanimate lifeless molecules.

People who do not believe in God also do not believe in creation. That’s why they tend to conclude that “nothing is created out of nothing, and nothing goes to nothing; there is only composition and decomposition.” But, the All-Powerful One has two ways of creating. The first way is through origination and invention and the second way is through composition and through art. He creates from out of nothing together with everything necessary for, again, nothing. In the second way of creating, He forms beings from materials of universe in order to show his delicate wisdom, perfection, and the manifestations of His Names. “O people! be careful of (your duty to) your Lord, Who created you from a single being and created its mate of the same (kind) and spread from these two, many men and women…” (Quran 4:1)

When we think about the lessons learnt from these examples and natural sciences with their special focus areas, we realize that every science somehow declare the Glorious Creator of this universe. However, there may not be an opportunity in school to discuss and go deep into the understanding of the Actions of the Creator. With the window of what sciences open to us about God, we can uncover the hidden truths.

Ali Fethi Toprak is a PhD candidate at Southwestern Medical Center, Texas University, Dallas.

Most, if not all, of water’s anomalous properties make life possible. To name a few of its many oddities, water is the only material that naturally exists in all possible forms (solid, liquid, and gas) on earth. Of all known chemical compounds, water has the second highest capacity to store heat, which is crucial for climate regulation and keeping living organisms’ body temperatures constant. Water is the second best heat-conducting liquid (after mercury), and this helps large masses of water to reach uniform temperatures quickly. Water has an astonishingly high heat of vaporization which eases body temperature regulation for humans and animals via providing a cooling system through sweating. This high heat of vaporization also prevents dehydration.

The absorption coefficient of water is a million times lower for the visible region of light than the rest of spectrum, a property which enables passage of the useful and prevention of the harmful rays from the sun, and makes the earth amenable to the accommodation of biological life. Furthermore, the greenhouse effect which keeps the Earth’s climate at moderation also stems from this aspect of water. Because the sunlight that is reflected from the Earth is mostly in the infrared region, it is effectively absorbed by the water vapor in the atmosphere due to water’s higher absorption of light within the non-visible regimes, and hence the heat does not escape from the earth.

Water is one if the best solvents, which is very important for cleansing. Finally (and thankfully), water does not display its peculiarity when it comes to taste. Such a “famously odd” molecule is somewhat ironically tasteless and odorless, and extremely easy to drink and consume.

“If We so willed, We would make it bitter and salty. Then should you not give thanks?” Waqi‘ah (56:70)

Although each of the aforementioned physical aspects of water deserves mentioning in its own right, from here on we will focus on water’s properties from a biological standpoint. To this end, we will first introduce some aspects of water, look at the interaction of water with bio-molecules, and finally elaborate on three particular biological examples (protein folding, cellular membranes and water channels), which demonstrate how such interactions provide the bases for life.

Life based on water

“We made every living thing from water.” Anbiya 21:30

Thanks to its abundance on earth, water is easily accessible and inexpensive. However, in the summer of 1986, Professor Michael Levitt of Stanford University spent almost half a million dollars on a tiny amount of water, that would hardly wet the point of a pin. Certainly, the money was not spent on the water itself, but the expenditure (it now costs about 50 cents to run such a simulation) reflected the cost of running a simulation on a cluster of supercomputers for two weeks to understand the interaction between water molecules and a particular protein. Eventually, the money turned out to be well spent. Although the same protein had been modeled before by a research group at Harvard University in 1977, the simulation had been carried out as if the protein were in a vacuum. Levitt and his co-workers realized that the previous attempt to model the proteins in the absence of water was a poor predictor of the real-life scenario. Likewise, earlier DNA simulations meant to model the double helical DNA in the absence of water had failed, Levitt and his colleagues also succeeded in simulating the DNA by adding water in the environment, and the water molecules were found to be interacting with nearly every part of the DNA. Levitt’s groundbreaking discoveries not only revealed the importance of the interaction between water and biological molecules, but also paved the way for computational biologists to simulate biological entities in the presence of their native watery media.

When a drop of oil is placed in water, it does not mix with water. Hence, oil and water are said to be immiscible. In contrast, sugar easily dissolves in water and forms a homogenous mixture upon mixing. Although not as obvious at first sight, the underlying principles which govern this phenomenon can explain how water can interact with biological molecules.

Materials can be classified according to their “water tendency”: the ones that tend to avoid water (e.g. oil), are considered hydro-phobic (hydro: “water,” phobic: “fearing”), whereas materials that mix well with water (e.g. alcohol) are called hydro-philic (or water-loving). Water’s particular molecular structure turns out to yield a non-uniform electron distribution, and thus makes water molecule highly “polar” (see Figure 1.a). As a consequence, polar or charged molecules prefer being close to water molecules, whereas the apolar or neutral ones tend to avoid them.

Many curious aspects of water stem from another fact-that water molecules can interact with each other through “hydrogen bonding” (see Figure 1b). Although the molecules in a liquid are highly disordered, hydrogen bonding gives water molecules some order even in the liquid phase. A molecule’s ability to cooperate in hydrogen bonding is very important for breaking (or formation) of hydrogen bonds, and affect two parameters (i.e. the “order” and the “energy”) of the system which determine the feasibility of a certain chemical reaction.

Actually, most, if not all, of the oddities of water are due to these two properties (water-tendency and hydrogen bonding). Furthermore, these two aspects determine a great deal of how water interacts with other molecules, and the way water enables the proliferation of life. We will now elaborate on some biological phenomena and try to understand them in the light of these aspects of water.

Protein folding

Proteins are biological molecules that carry out the vital tasks of life. In the cell, proteins are initially synthesized as linear chains of amino acids ranging in size from a few to several thousand amino acids in length. Subsequent to synthesis, a linear chain spontaneously folds into a particular three-dimensional (3D) form (see Figure 2). This precise fold is essential for the execution of protein’s specific function (see Figure 3). As simple as it may sound, protein folding is currently one of the biggest questions in biophysics.

Researchers are working hard to be able to devise principles to estimate which 3D fold a certain linear amino acid sequence adopts, and what functions the eventual 3D structures execute. Although these questions related to the protein folding phenomenon are still far from being totally understood, some clues have been discovered.

In 1969 Cryus Levinthal stated that an average size protein would fold within about 1030 times longer than the expected lifetime of the universe if it were to fold via sampling all possible conformations even if the conformational sampling is very fast (e.g. a millionth of a millionth of a second for each conformation). This obviously is not what happens in reality, and the experimentally observed folding times are within milliseconds (a thousandth of a second) – second regime. This discrepancy between the estimated and the measured timescales is referred to as the “Levinthal Paradox.”

Consequently, proteins cannot rely on randomly sampling all the possible conformations to fold, but the folding must rather be a driven and directed process. Scientists hypothesize that water comes to the rescue at this point. As the linear protein chain is being synthesized, water-hating amino acids try to bury themselves away from water as soon as possible. This leads to the rapid collapse of the linear amino acid chain into a compact structure where hydrophobic regions are protected from water (see Figure 2c). This initial compaction which is provided by the interaction with the ambient aqueous medium is thought to be the key step in achieving folding within reasonable timescales. After the first rapid compaction, the protein adapts its final structure by sampling a much smaller number of possible conformations.

Simultaneously, hydrogen bonding helps the stabilization of certain folds with respect to other possible structures and contributes to the folding process. Eventually, the functional 3D fold is thus realized from the nascent linear protein chain.

Cellular compartmentalization

“He has let flow forth the two large bodies of water, they meet together, (but) between them is a barrier, which they do not transgress (and so they do not merge).” (Rahman 55:19-20)

Compartmentalization is an important feature of life. First of all, the boundary of a cell must be well-defined and well-controlled. Secondly, different tasks are carried out by specialized compartments (so called organelles) within most of the cells. The major design principle of the cellular boundaries depends on the immiscibility of water and oil. The subunits of cellular membranes are “lipids” which simply are oil-based molecules. A lipid molecule has two parts: A water-loving “headgroup” and two water-fearing “tails”. Because of the dual water-tendency of lipids, they can self assemble into bi-layers (see Figure 4 a and b), which eventually form enclosed structures. Thanks to the properties of water, this compartmentalization is readily achieved.

The cell membrane thus formed is impermeable to ions, and many chemical agents important for sustaining the cellular functions. Although such a barrier is essential for holding the cell contents as well as maintaining intracellular balance, material exchange between inside and outside of the cell is also an indispensible trait for carrying out the vast majority of vital processes (nerve impulse formation and transmission, cell signaling, nutrition, etc.). In order to achieve well-controlled material transport across the membrane, the cell membrane is decorated with various proteins that function as “channels” (see Figure 4c). These channel proteins come in different flavors and show specificity towards different chemicals. For instance, the channel protein for the potassium ion (K+) only allows the passage of potassium ions, whereas the sodium channel only lets sodium (Na+) through. Other channels have “gating” mechanisms that enable the channel to be “open” or “closed” depending on the need for the transport to happen. Although the specificity and gating mechanism of every channel protein relies on a unique ingenious design principle which deserves detailed mention in its own right, in the rest of the article we will focus on the water channel, for it once again exemplifies the perfect harmony between water and the bio-molecules.

Aquaporin: The water channel

Almost 170 liters of water is recycled in the human kidney on a daily basis, and this requires that kidney tissue possesses high water permeability. Since water cannot diffuse in and out of the cell membrane very rapidly for the reasons given above, reconciliation of the enormous daily flux of water in the kidneys has been a long-standing puzzle. The discovery of water channels (also known as “aquaporin”) by Peter Agre in 1992 resolved the mystery, and this finding was awarded the Nobel Prize in Chemistry in 2003. It is now known that the recycling machinery in the kidney chiefly consists of millions of aquaporins. Like other channel proteins, aquaporins also display selectivity: water is effectively transported across aquaporins, whereas the passage of other ions and miscellaneous agents is not permitted.

However, how this selectivity is achieved presented another riddle: Hydrogen is smaller than water and can move through the smallest opening. How, then, is the hydrogen selected against, while water is allowed? It was also well known that water molecules which are ordered within the channel constriction (see Figure 5) normally form a “proton wire” through which the hydrogen ions (i.e. protons) can easily flow just like an electrical current flows along an electrical wire. Thus, as water is transported across aquaporins, hydrogen ions should in principle move rapidly in and out of the cells through the chain of ordered water molecules (i.e. the proton wire) in an uncontrollable manner. This would cause an imbalance in the cellular environment, and most likely would lead to cell death.

The answer came from a computer simulation of aquaporin by Emad Tajkhorshid and Klaus Schulten at the University of Illinois at Urbana Champaign. They found that the water molecules change their orientation (see Figure 5) as they spun through the water channel. This rotation was achieved via water molecules’ specific interactions with the amino acid residues in the channel. Thanks to this orientation, the formation of the proton wire is disrupted (just like a break in an electric circuit) and the hydrogen ions are not permitted through the channel, while rapid water diffusion takes place. The interaction between water and aquaporin thus provides just another reason water is rightfully considered the cradle of life.

Conclusion

“There are only two ways to live your life. One is as though nothing is a miracle. The other is as though everything is a miracle.” Albert Einstein

… and that He sends down water from the sky, and revives with it the earth after its death. Surely in this are signs for people who will reason and understand. Rum 30:24 

References

1. Gedik, N. “The Miracles of Water,” The Fountain, Issue 43, January–March 2005.

2. Ileri, R. “Water and Vitality,” The Fountain, Issue 2, April-June 1993.

3. Unal, Ali. The Qur’an: An Annotated Interpretation in Modern English, The Light, Inc. NJ: 2005.

4. “Simulating Water and The Molecules of Life,” Scientific American, November 1998.

5. Errington, J. R. & Debenedetti, “P.G.” Nature, 409, 318–321, 2001.

6. Water, Wikipedia.

7. “Mysteries of Water,” Physics Today, June 2003.

8. Sener, Hamdi. “Mikroalemdeki Canli Motorlar” (Living Engines in the Micro World), Sizinti, September 2005.

9. Figures are modified from: Chemical polarity, Wikipedia
Hydrogen bond, Wikipedia
http://www.ccl.net/cca/documents/dyoung/water/
http://www.helsinki.fi/~jtvaara/images/water.gif
“Inner Life of The Cell” animation, http://multimedia.mcb.harvard.edu/
“Molecular Biology of the Cell,” 4th Edition; Bruce Alberts et al.
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