Cancer is a prevalent disease among humans and animals, affecting millions of lives across the globe. It can be caused in a variety of ways and can affect virtually every part of our bodies, ranging from skin cancer caused by prolonged exposure to the sun’s harmful UV rays to lung cancer that results from carcinogenic substances smokers inhale. However, plants do not die of cancer despite sometimes being exposed to the sun for over a thousand years – and they do not use any sunscreens!

Humans and animals who live to a certain age are very likely to get cancer one day. We see this situation mostly in our pets which have been specially bred and protected from predators and diseases. Cancer has become part of our lives and remains a top world health priority. The probability of prostate cancer is roughly 80% in 80-year-olds, 90% in 90-year-olds, and 100% in 100-year-olds. However, these statistics yet again do not apply to trees.

What is cancer?

Cancer is a disease caused by the uncontrolled growth of cells that have become abnormal in a part of the body. These abnormal cells are not foreign invaders that have entered our bodies from outside but are instead our own cells. However, in time, various factors such as radiation, viruses, and chemical substances that they are exposed to cause the accumulation of errors, or mutations, in the genetic codes of cells. Some of them then acquire very different characteristics and become alien to their own body.

With old age, errors arise in the genetic code in an increased rate when our cells divide by copying their own DNA. External factors, such as “free radicals” and various radiations that affect our DNA, play a role in these errors. For young people, when there are too many errors in a cell’s genome, a process called “apoptosis” takes place after which faulty cells die before they can multiply in a potentially cancerous manner and forming a tumor. However, sometimes these accumulated errors cause the cell’s growth process to become stuck in the “on” position, and the cell begins to grow and divide continuously. Cells that emerge with out-of-control divisions ignore the commands coming from the healthy cells of the body, continue to grow and reproduce according to the erroneous commands from the cell’s disrupted genome. This situation lasts until death.

What is a tumor?

Cell growths that result from defective genome proliferation will eventually form a mass called a tumor. Some cells grow very slowly and stop at a certain size after a while and do not spread anymore and are called benign tumors. Masses formed by fast-growing, defective (cancerous) cells are known as malignant tumors. Cells that detach from malignant tumors and grow rapidly can attach to another organ where they will begin to grow again when they enter the bloodstream. The process by which cancerous cells start from a tumor and spread all over the body to different organs is known as metastasis.

Why does this process not happen in plants?

One of the most destructive features of cancer when it enters metastasis is the mobility of malignant cells to varying degrees according to their type. Blood vessels, i.e. the transportation pathways of the circulatory system, act like a highway for cancer cells. As the blood vessels surround the entire body, a single cancerous cell can travel to and settle almost anywhere in the body, from the toes to the head.

Plant cells have a vital feature that is different from human and animal cells. In plants, cells do not change their locations because their cells are surrounded by a very rigid, strong, and impenetrable wall outside of normal plasma membranes. Cell walls are made of cellulose, which constitutes the main substance of plants, and form the wooden structures that ensure the plants stand upright and harden while at the same time locking each cell in place and preventing it from migrating within the organism.

Another important difference that is unique to plants is that they do not have blood circulation in which cells are carried; they have a circulatory system in which only water and food are carried. This system is often used to pump water from the roots to the leaves and to transport organic products such as sugar, which is a product of photosynthesis, from the leaves down. Therefore, there are no blood cells or immune system cells in these carrier channels, which are known as wood and roe tubes (xylem and phloem), in plants.

In addition, animal cells are specifically employed in tissues and organs such as muscle, bone, liver, and skin during embryonic development. Thus, when they divide only new cells of the same type are created. Tumors that occur in animal tissues can metastasize into different tissues and disrupt different organs. We can think of animal and human biology as a very complex system in which each cell, tissue, and organ has a task and purpose. In such a system, all elements work in cooperation for the continuation of life. This system is of a kind of irreducible complexity. A human being cannot live without organs like brain, heart, or lungs, while plants, on the other hand, have fewer simpler internal structures which are not as vital. When plant cells divide, they retain their ability to form new cells of any type. This is called totipotency.

In plants, every necessary structure can be recreated from the few tissues they have. For this reason, a gardener can grow new plants from the roots, branches, or leaf parts of a plant.

Plants are equipped with very powerful antioxidants to protect them from the sun’s harmful rays and mutations that may be caused by radiation. Therefore, tumors can develop only due to bacteria, viruses, fungi, parasites, and insects. For example, in a situation that we can call “information confusion” that occurs when Agrobacterium Tumefaciens bacteria insert some of its DNA into the plant’s DNA, an anomaly occurs in the plant’s genome. Cells that go through a rapid growth process and form tumors are not normally classified as cancer, since they simply remain in that area and cannot be transported elsewhere. Since the tumors cannot spread to the whole plant, they may cause only minor distress at most in a specific area rather than a fatal disease such as cancer. Just as the plant continues to grow around a rock that it encounters, it grows around the tumor as well. The tumor can continue to grow for years, but does not spread to the rest of the plant, meaning there is no metastasis.

In summary, plants can also be cancerous, but a cancerous tumor is not a deadly threat to a plant, as its cells are immobile and do not have vital and complex organs like humans and animals. Thanks to the cellulose walls gifted to the them, plants continue their role in the ecosystem by continuing to grow with healthy cells around the tumor as if nothing had happened.

References

• Luis Villazon. “Can a plant die of cancer?” www.sciencefocus.com/nature/can-a-plant-die-of-cancer
• Sam Westreich. “Do Plants Get Cancer?” medium.com/@westwise/do-plants-get-cancer-60eb435c6d1a
• Stuart Thompson. “Plants couldn’t run away from Chernobyl—but that’s what saved them. Why plants don’t get cancer.” www.popsci.com/chernobyl-plants-radiation-cancer

{module Science Square (Issue 128)}

First miniature human heart printed

Noor N et al. 3D Printing of Personalized Thick and Perfusable Cardiac Patches and Hearts.  Advanced Science, April 2019.

In a major breakthrough, researchers have “printed” the world’s first 3D vascularized engineered heart using a patient’s own cells and biological materials. This could have huge repercussions for human health: the World Health Organization said that last year, ischemic heart disease and stroke were the world’s leading cause of death for both men and women. Heart transplantation is currently the only treatment available to patients with end-stage heart failure. Given the serious shortage of heart donors, scientists have been trying to develop new “3D organ printing” approaches to regenerate the diseased heart. Past studies were only able to print simple tissues without blood vessels. The new study showed for the first time that an entire heart with cells, blood vessels, ventricles, and chambers could be successfully engineered and printed. The researchers first took a biopsy of fatty tissue from patients and separated the cellular and a-cellular materials of the tissue. While the cells were reprogrammed to become pluripotent stem cells, the extracellular matrix – a 3D network of extracellular macromolecules such as collagen and glycoproteins – were processed into a personalized hydrogel that served as the printing “ink.” After being mixed with the hydrogel, the cells were then robustly differentiated to cardiac or endothelial cells to create patient-specific, immune-compatible cardiac patches with blood vessels and, subsequently, an entire heart. The heart was 3D-printed in about three hours and was too small for humans. It was the size of a rabbit’s heart (~ 2.5 centimeters). But it is completely biocompatible and, most importantly, matches the patient, which reduces the chances of organ rejection inside the body. A human-sized heart might take a whole day to print and would require billions of cells, compared to the millions used to print these mini-hearts. While it’s not clear if a printer can produce hearts that are equal or superior to human ones, perhaps by printing patches there will be a possibility to improve or take out diseased areas in the heart and replace them with something that works. Researchers hope that maybe in 10 years, there will be organ printers in the finest hospitals around the world, and these procedures will be conducted routinely.

Bacterial factories for spider silk

Zhang F et al. Synthetic Biology for Microbial Production of Protein-based Materials, the American Chemical Society (ACS) National Meeting & Exposition, Spring 2019.

Spider silk has always fascinated researchers due to its lightweight and superior strength and numerous applications in areas such as drug delivery, smart textiles, and artificial muscles. It is one of the strongest natural materials in the world. It is thinner than a human hair, but its strength is more than that of steel, pound for pound. Since farming spiders is incredibly inefficient, scientists have been trying for decades to find a way to mass produce the material from genetically modified bacteria, yeast, and even goat milk, but these efforts have always fallen short. The biggest challenge was that the genetic information for dragline silk is a long string of repeating DNA, and, in previously tested organisms, cellular machinery arbitrarily alters or chops up such DNA sequences. To circumvent this problem, researchers precisely separated the repeating DNA into bits and inserted each repeating piece separately into bacterial genome. These smaller DNA pieces produced small peptides that ended up combining in bacteria and formed a strand of silk. The researchers also added to the end of each strand a chemical tag that glued the individual fibers together. This method was able to produce 2 grams of spider silk for each liter of bacteria and the resulting material behaved exactly like dragline silk. Its tensile strength was measured at 1.03 gigapascals, about the same as for naturally produced dragline silk. The engineered silk’s toughness measured 114 megajoules per cubic meter, compared with around 100 megajoules for silk made by spiders. And the engineered silk strands could stretch 18 percent before breaking, the same as natural dragline silk. The new silk was developed in part with NASA funding for applications such as giving astronauts a means of producing tough materials while on Mars. But the substance could be used in designing stronger materials for robotic, medical, or textile applications.

Electricity from falling snow

Ahmet A et al. All printable snow-based triboelectric nanogenerator. Nano Energy, April 2019.

Researchers have designed a new device with which we can now obtain electricity from falling snow. This new energy conversion method could become a new source of electricity in the future, especially in remote areas, as it does not need batteries. Researchers called it a Snow-based TriboElectric NanoGenerator, or Snow TENG. It is inexpensive, small, thin, and flexible like a sheet of plastic. After starting a charge from static electricity, energy is generated from the exchange of electrons. Snow is already positively charged by giving up its electrons, while silicone, a rubber-like material which consists of silicon atoms and oxygen atoms, is combined with carbon, hydrogen, and other elements to be negatively charged. When the positive-charged snow falls onto the surface of the silicone, the charges interact, and the Snow TENG captures the charge, which allows it to turn snowfall into electricity. 30% of Earth’s surface is covered by snow each winter, which is also the time when solar panels, one of the most reliable renewable sources of energy, aren’t very effective. Snow accumulation reduces the amount of sunlight that reaches the solar array, which makes them unable to operate. Snow TENG could be integrated into solar panels and provide a continuous power supply, even at a time when it’s snowing. Researchers used 3D printing to design the small device. It consists of a layer of silicone and an electrode which can capture the electric charge. Given that silicone is widely used in the industry, this method could dramatically reduce the global costs of producing electricity.

We are all aware of the fact that there is certain rhythm and order in the movement of the sun and the earth, as well as other planets along their pre-assigned orbits. This order has ongoing without a glitch for possibly billions of years. The day and the night become longer and shorter on a schedule, and this is how we can develop calendars by calculating seasons, months, and days.

The movements of celestial bodies impact in multiple ways the biosphere in which we live. Trees shed leaves or bloom, some animals hibernate, and others enter reproduction season.

Time advances not linearly but in cycles. The internal systems by which the metabolisms of living things are organized are made to work according to numerous biological clocks that depend on the cyclical nature of time. These biological clocks are sometimes based on the length of a day and sometimes on long cyclical patterns that may span years. Periods of sunspots followed by explosions on the surface of the sun, for example, cause the reproduction cycles of populations of lynx and hare to peak every 11 years. This cycle is also tied to an increase in the production of wheat and certain species of fish breeding in abundance. The internal clock of the human metabolism is likewise organized during the day.

Scientists have long since noticed and started to research the different reactions of the human body to different time intervals throughout the day. It was realized that pains eased during certain times of day and intensified during others. There are also rising and falling cycles for hormones and the nervous system. These coincided with periods of hunger, meals, and sleep.

It has been found that certain changes occur in the physical and mental makeup of humans during the year, seasons, month and day. Researchers agree that every human has a unique physical and mental clock, but there are generally broad similarities. The scientific field researching these is called chronobiology. Researchers in chronobiology have demonstrated that certain changes occur, according to time periods, in the endocrine and autonomic nervous system as well as the body’s water and salt balance.

Other studies have focused on biological changes with respect to space. The regulation of the body’s biological rhythm is found to be influenced by the movements and positions of the earth on its own axis, the moon around the earth, and the earth around the sun. As the atmospheric environment changes, so do living things.

Towards the end of the 1960s, scientists found that a synthetic corticosteroid drug called methylprednisolone was more reliable for treatment of arthritis and asthma when taken in the morning rather than at other times. “These rhythms might affect responses to cancer treatment,” says Eric Holland, a neurosurgeon at Fred Hutchinson Cancer Research Center, adding that there are optimal times for administrating radiation in mice.

A forty-three-year-old patient with 27 tumors in her liver whose drug treatment for colon cancer did not work volunteered for a trial and recovered from cancer after rescheduling the administration of her drugs. Oncologist Francis Lévi was so amazed by this effect on the patient that he became a supporter of chronotherapy, or time-cycled treatment. To Lévi, who works at Warwick Medical School in the United Kingdom, timing can prove even more important than dose. In the trial, the patient was first wired up to a device like a clock so that metabolic rhythms could be better monitored. The patient had extremely regular sleep-wake cycles, which Dr. Lévi believed was likely to have contributed to the success of the treatment. This novel understanding did not spread before because researchers could not explain molecular foundations of daily rhythms, or circadian cycles, until 10 years ago, and clinical data was inconsistent.

Lévi and his team randomly divided 186 chemotherapy patients into two groups. They administered medicine to one group in accordance with the participants’ biological clocks and to the other group according to the standard procedure. More than 50% of the former responded well, whereas the rate remained at only 29% for the latter. Another study found that 298 patients who had heart operations in the morning were twice as likely to have unsuccessful operations and develop complications as compared to 298 patients who had operations in the afternoon. To prevent the effects of the surgeon’s selection of patients, the same surgeons operated both in the morning and in the afternoon.

The 2017 Nobel Prize for the field of physiology was awarded to three American biologists, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young, for their study into biological rhythms. Their research presents remarkable insights into the reasons why the biological rhythms of plants, animals and humans are created in coordination with the movements of the earth. The researchers used the fruit fly, an exemplary organism, and found the genes that controlled its daily biological rhythm. Discovering that these genes initiate the secretion of a protein that accumulated overnight and dwindled during the day, the researchers revealed that these proteins caused a mechanism made to work in a certain rhythm when the time was right. It was like a watch had been set inside the fruit flies’ cell.

It is estimated that approximately 80% of our genes follow night and day rhythms (and also possibly seasonal rhythms). Indeed, it has been identified that fits of asthma and epileptic seizures develop according to certain daily rhythms. The products expressed by the genes that are active in most tissues peak early in the day and in the afternoon and reach lows after dinner and before bedtime. All these activities are carried out by the “molecular biological watches” written in our genes. If we can better understand our internal clocks, researchers believe they could discover breakthroughs in the treatment of up to 150 diseases, including cancer.

The time machine

Many tissues in the body have their own time schedules arranged by regular cycles in which numerous innate “clock genes” envelop the body like a net. The timing of all these clocks can have a powerful impact on metabolic activity, the increase in the number of immune cells, and many other things. “The best advice I can offer is don’t mess with your body clock,” says Professor Derk-Jan Dijk, director of the Surrey Sleep Research Center in the city of Guildford, England. [1]

The biological clock is an extraordinary system. A group of neurons in the hypothalamus in the brain, called the suprachiasmatic nucleus, are assigned as the central clock for all these activities in the body. The signals from this region play a role in initiating and finalizing the activities of the genes, which channel drugs to their molecular targets and help produce enzymes that destroy drugs. “Clock” genes are found virtually in every organ and tissue, and they are particularly important during cancer treatments, because interventions performed during such critical processes as the cycle of cellular division and growth and repair of DNA damage become significant for killing cancerous cells.

Cisplatin, an effective drug used for almost 50% of solid tissue cancers, kills malignant cells by binding to their certain parts, yet because the drug is toxic to the kidneys, lungs, and nervous system, efforts have been made to develop less toxic versions. Just as a cell develops cancer due to DNA damage, so is the destruction of the cancerous cell started by damaging the cell’s DNA. For this reason, some drug trials focus on blocking the DNA repair of the cancerous cell.

Observations made on the appearance and repair of DNA damage showed, as expected, that DNA damage was repaired more easily during certain periods of the day, leading to the hope that cancer can be treated through DNA repair if drugs are administered in tandem with this cycle. If optimal periods could be established for numerous normal cells to repair their DNA damage, administration of drugs can both optimize the useful effects of drugs and minimize toxicity of drugs with toxic properties.

The human organism and cells are not static, but dynamic. The behavior of our cells changes dramatically before and after a meal. Similarly, the movement and frequency of numerous materials circulated in our body when we are sleeping are different from when we are awake. Therefore, if the amount of a material doubles after lunch followed by a cup of coffee and if the material negates a drug taken by a patient, then that drug can be administered when this material is at its lowest in the body. For example, if the material is at a minimum at two in the morning, the drug can be given at that time, ensuring that the effect is maximized.

The studies into “man, the unknown” are bound to lead to many more discoveries about both treatments of diseases and the knowledge, power, and wisdom waiting to be found in the creation.

Note

1. https://woolcock.org.au/new-2/why-you-shouldnt-mess-with-your-body-clock-expert

References

• Leder, K., Pitter, K., LaPlant, Q. (2014). Mathematical Modeling of PDGF-Driven Glioblastoma Reveals Optimized Radiation Dosing Schedules. Cell. Cilt 156, Sayı 3, s. 603-616.
• Lévi, F., Zidani, R. & Misset, J.-L. (1997): Randomized multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 350, 681–686.
• Peeples , L. (2018). Medicine’s secret ingredient — it’s in the timing. Synchronizing drug delivery with a patient’s body clock can yield clear benefits. But will the data be enough to overcome long-standing hurdles? Nature 556, 290-292 (2018).
• “Why You Shouldn’t Mess with Your Body Clock: Expert,” woolcock.org.au. August 7, 2018.

Radiation, which refers to emissions of light or particles, is a type of energy transfer. Radiation takes place at any given moment in the environment or the body. Among sources of radiation to which humans are exposed daily are sun rays, radio waves coming from devices such as mobile phones and TV sets, appliances such as ovens or irons that emit heat, and medical machines such as ultrasounds. The radiation emitted from devices and machines do not cause ionization. Ionizing radiation is made up of high-energy wavelengths or particles, and this is the kind of radiation we get from x-ray, CT, and nuclear imaging. This is used to penetrate tissue to reveal the body’s internal organs and structures. Ionizing radiation can damage DNA, and when our cells cannot fully repair the damage, this may result in DNA mutations.[1] The radiation which poses real danger to humans and has the power to ionize is when radioactive—or unstable—atoms decay and emit alpha (α), beta (β), and gamma (γ) rays.

The earth, air, water, and all living things are more or less radioactive because radioactive atoms are everywhere. The average person is annually exposed to radiation levels of 2.6 – 10 mSv (millisievert), which is not that alarming. The maximum limit recommended for people exposed to radiation for occupational reasons is 100 mSv. The lungs of a person who smokes one pack of cigarettes a day are exposed to an annual radiation of 106 mSv.

How can we protect ourselves?

It is recommended by the World Health Organization that children younger than 16 should not use mobile phones; when they do, their calls should not exceed 10 minutes. When purchasing devices, you should also take into account its SAR (Specific Absorption Rate). Prefer devices with a SAR<1 W/kg. It is also recommended to unplug electrical devices when you are not using them, to keep electrical appliances as far away from your head as possible, use the hairdryer for short periods and in intervals, and to avoid using mobile phones for long conversations (or use headphones!).

It’s also worth reconsidering whether using radiation-emitting devices such as mammography, x-rays, or ultrasounds are absolutely necessary. In 2010, the British Department of Health and Social Care banned using tomography for screening purposes. Another study in the US found that one in ten people are exposed to high levels of radiation because of medical tests.

The average radiation rates (mSv) a person was exposed to during use of certain imaging devices is as follows:

Researchers also found that employees in nuclear power plants were exposed to amounts of radiation that far exceeded allowable amounts.

Beware of radon

The natural radiation humans are exposed to most is the gas radon. Some matter with radioactive atoms such as uranium and thorium – both present in the earth since its birth – emit radon, which seeps through the earth and into the walls of houses and through gaps in plumbing. It is recommended to air houses at least 15 minutes every 24 hours as the only way to be protected from radon.

The resistance of living things

Creatures have been created with different forms of resistance to the elements, including radiation. For example, dogs have a lower resistance than humans, while many other creatures such as rabbits, tortoises, and fruit flies have a higher resistance. And then there is the cockroach, which can survive even a nuclear attack. The lethal radiation dose for cockroaches is an incredible 670- 1000 Sv, whereas it is 6-8 Sv for humans.

Scorpions are also much more radiation-resistant than humans. They can withstand up to 1500 Sv, an amount that is 250 times the maximum dose humans can take. Studies have found a correlation between the strength of a scorpion’s venom and their resistance to radiation. The greater the amount of venom, the greater the resistance they have. The presence of the neural transmitter serotonin supports this view.

Are humans radioactive too?

Humans contain trace amounts of radioactive atoms, namely uranium (²³⁸U), potassium (⁴⁰K), and carbon (¹⁴C). An 80 kg human has natural radiation of 8000 becquerel every second, which is equal to 100Bq per kilogram. This amount is not high enough to cause any worry. The human body has 40 trillion cells on average, and every cell has about 100 trillion atoms. The proportion of the radiating atoms in the body is about 8000/4×10²¹.

Precision protection

The radioactive atoms in the body with the highest probability for carcinogenic effects are potassium (⁴⁰K) and carbon (¹⁴C) atoms. The decomposition that leads to cancer stems from mutations in genes, but the molecules that are the building blocks of genes do not have potassium atoms. The likelihood that a cell gets harmed is very low: it is necessary that the particles emitted from the radioactive potassium atom crash into the DNA molecule and harm it, which is as unlikely as threading a needle when blindfolded. The DNA is precisely protected inside the nucleus located at the center of the cell. If we consider the fact that the average diameter of a cell is about 10 microns (1 micron is one-thousandth of a millimeter), we can better appreciate how little space DNA occupies.

Radiocarbon atoms (¹⁴C), on the other hand, might be present in DNA molecules, and they are more dangerous because the emitted particles are more likely to find the target despite having weaker radioactive properties than potassium. A radioactive carbon atom turns into a nitrogen (¹⁴N) atom and may thus cause a chemical change in the DNA. In other words, the carbon atom is possibly to blame for the unexpected development of cancer.

The likelihood of harmful radioactive particles hitting a person’s DNA is low, and the protective system provided for it lowers the likelihood of developing cancer even more. New DNA molecules that form during DNA coupling are repeatedly checked by inspector enzymes. If there is an error, it is detected and then corrected. The broken code is taken out to be replaced with the correct version. Meanwhile, all these steps are checked by other enzymes assigned to the task. More errors might be made in the newly produced DNA molecule because of external factors. Yet ribosomes in the cell start to produce repair enzymes, as per the instructions from the DNA.

When thinking about all the protective factors that have been coded into the DNA for our survival against the 8000 radioactive activities that occur in our body every second, one cannot help but feel awe for the infinite mercy and wisdom that operate in our lives.

References

• http://time.com/5069317/california-mobile-phone-radiation/
• https://www.health.harvard.edu/cancer/radiation-risk-from-medical-imaging
• Choppin, G. et al., Radiochemistry and Nuclear Chemistry, Oxford: Elsevier Science & Technology, 1995.
• www.physics.isu.edu/radinf/natural.htm

[1] https://www.health.harvard.edu/cancer/radiation-risk-from-medical-imaging

Embryonic stem cells are cells in the early stages of embryonic development when a fertilized egg cell is divided first into two cells and then into four, eight, and sixteen. Each grows into a brand new cell type and multiplies as per the codes present in its DNA program as tissues form and organization starts. 

After twenty years of research and accompanying debates on the human embryo, we are finally on the threshold of both reshaping our present concepts in biology and moving on to clinical case studies. The first human embryonic stem cells were produced in 1998. Studies researching the question, “Can we treat diabetes by reprogramming the DNA in these cells at the beginning of life?” switched first to how human genes worked and which genes are responsible for the development of particular tissues and then to the embryonic stem cells for these areas and ultimately to replacing or reprogramming a “faulty or deficient” gene.

The most controversial topics in genetics and embryonic studies are related to bioethics. Many scientists are grappling with questions like whether is it ethically correct to intervene with the genetic programming of a fertilized human egg (zygote)? If so, what should be the limits? Are we trespassing a divine domain?

Embryonic stem cells have been an excellent source of information that we lacked throughout history about how living organisms started to develop. Like astronomers who trace their knowledge to the Big Bang in order to obtain fundamental information about the origin of the universe, biologists have been researching how the molecules in a single cell went through sequential and planned changes, how they transformed and acquired new functions that triggered the mind-blowing developments in diverse, miraculous living organisms. Scientists have found out how primordial embryonic cells transformed into more than 200 cell types that constitute various tissues and organs. The number of studies has skyrocketed about which molecule types can be used to regenerate the damaged tissue, say, after a traffic accident. Embryonic studies that focus on the regeneration or reparation of medulla cells (spinal cord) have been a source of hope for some patients with permanent paralysis because of a broken back injury or severed spine in a traffic accident or those who are still stranded in wheelchairs. Similarly, the preliminary findings of research into Parkinson’s and diabetes are extremely promising, and a new study reports of two blind people with macular degeneration (which causes blindness) who have been treated.

Initial studies

In 1981 researchers successfully obtained stem cells from a rat embryo culture. They soon realized that the cells held a secret potential: they could grow into 200 different types of cells. Later Wisconsin-Madison University biologist James Thomson derived stem cells from primates for the first time. Three years afterwards, Thomson derived the first human embryonic stem cells from donated but unused embryos.

The increasing number of research studies into embryonic stem cells sparked off intense debate both in religious circles and among the science community that care passionately about the sanctity of humans. Allegedly, lab studies were conducted on human embryos without restrictions, which were grown until tissues and organs formed but were then killed. In 2001, the US president George W. Bush slashed federal funds, stating that stem cell research was not strictly ethical. Deriving embryonic cells was banned in many countries including Germany and Italy. In other countries, however, studies went full speed ahead. Indeed, reports flooded in about stem cells grown by researchers in Australia, Singapore, Israel, Canada and the USA into nerve cells, immune system cells, and heart cells.

Before long, a new idea emerged about transferring new cells into the egg cell – like nuclei of body cells used in cloning Dolly the sheep – to produce various tailor-made, fully DNA-compatible tissues and organs, as they had the same genome as the donor’s. It became a topic of everyday conversations that spare organs could be cultivated for the human body just like spare parts of cars or other machinery were produced to replace a faulty or damaged part. In fact, if it were not for claims such as “creating a new human” there would be no objections against producing a kidney, lung, or heart from the DNA of a patient and thus overcome the major problem of tissue rejection in transplantation of organs.

If faulty or defective genes could be removed and replaced by healthy genes in the DNA of stem cells, many incurable genetic diseases could easily be fixed and many prospective parents who avoid having a child because of a defective gene they carry would welcome the development enthusiastically.

We are on the threshold of reshaping our present concepts in biology and moving on to clinical case studies. Embryonic studies have been a source of hope for even patients with diseases like paralysis and blindness.

Just in time and in the right amount

Embryonic stem cells are cells in the early stages of embryonic development when a fertilized egg cell is divided first into two cells and then into four, eight, and sixteen. Each grows into a brand new cell type and multiplies as per the codes present in its DNA program as tissues form and organization starts. It is most mysterious and miraculous that the molecules that lead a stem cell to transform into a new type of cell are synthesized at exactly the right moment and in the precise amount.  Scientists are currently trying to figure out which molecule leads a cell to become a nerve, muscle, or bone cell when attached to it. They are likely to decode the molecules by monitoring the tissues that remain undeveloped because of missing genes resulting from DNA mutations observed in certain genetic diseases.

The new field that has developed in the last two decades called regenerative medicine is predicated on tapping into the potential of stem cells by repairing missing or faulty tissues, or completing a link in the chain necessary for the functioning of a dysfunctional metabolic process. In 2006, stem cell biologist Shinya Yamanaka of Kyoto University in Japan successfully transformed adult rat cells into an embryonic state. The following year, human body cells were transformed into embryonic stem cells. The ensuing research has led to the acknowledgement that it was theoretically possible to transform stem cells into any cell type, a promising cure for diseased embryos that have genetically missing parts.

The major problem, however, is keeping these delicate cells alive in a culture medium. In 2007, Yoshiki Sasai discovered a molecule called rock inhibitor that nourished the cell colonies he grew. The success rate in generating new cell colonies rose to 27%. Parmar from Swedish Lund University heralded “a new golden era” by producing new neurons from embryonic stem cells for the treatment of Parkinson’s.

As new techniques were developed for producing cells fast and reliably, these cells turned out to involve a very low risk of developing cancer. “We don’t yet know how this hidden power and balance that can be transformed into any cell type is controlled,” states Hiromitsu Nakauchi, a stem cell biologist at Tokyo University who researches making blood platelets out of stem cells derived from the embryo or somatic cells.

Experiments are underway that aim to treat disorders by activating stem cells stored in the body that have not yet differentiated through the help of proper stimulating molecules. 

Miraculous differentiation

As the techniques for producing and feeding stem cells got easier, researchers aimed at growing and forming tissues and organs. A connective tissue or an outer covering like the skin that lacks a shape but takes the shape of the underlying muscles and bones can be produced even in a Petri dish and then transplanted to a burned or missing area of the skin. The present aim is the production of organs such as the kidney or the heart that has a particular shape and is made up of a number of different tissues. If the correct signal molecules responsible for cell division and differentiation can be identified and readily used where necessary and at the right amount, then organs including any type of tissue can be produced. Researchers like James Wells at Cincinnati Children’s Hospital in Ohio have tested the damage of drugs on intestines by using the partial intestines they developed from stem cells rather than administer them to normal humans, thereby hailing the imminent age of intestine transplants.

In 2004, the doctors who did tube baby experiments for a patient in Chicago known to have a genetic disorder started to produce a series of stem cells from generated embryos. They made models at the cellular level of the emergence of such genetic disorders as thalassemia, Huntington’s disease, Marfan syndrome, and muscle dystrophy. In 2007, they used embryonic stem cells to suppress molecular changes that trigger mental disorders caused by a genetic disorder called fragile X syndrome.

Research shows that multipotent (mesenchymal) cells stimulated at the outset of tissues are even more promising than embryonic cells with respect to diseases because it is easier to repair damaged or missing tissue by guiding them. However, it is essential in a genetic disorder that cells derived at the beginning of the embryonic stage should be used in order to replace faulty genes with healthy ones and address the disorder at its outset.

Experiments are underway that aim to treat disorders by activating stem cells stored in the body that have not yet differentiated through the help of proper stimulating molecules. In this way, as many as ten illnesses are likely to be treated, some of which include diabetes, macular degeneration in the eye, and neurodegenerative diseases such as Parkinson’s.

Douglas Melton from Harvard Stem Cell Institute in Cambridge has worked for fifteen years to transform embryonic stem cells into insulin-producing β-cells. He has produced pancreatic cells that sense glucose and produce insulin and he hopes to transplant them to end the dependence of patients of diabetes type-1 on insulin shots. The last obstacle remains to be the introduction of these cells to the system so that they are not destroyed by the patient’s immune system.

Clinically, it is believed that stimulated multipotent cells have a greater advantage than embryonic cells because the produced cells and tissues have the same DNA as the patient and thus do not cause any immune reaction when they are transplanted. The problem for many genetic disorders including type-1 diabetes is that the patient has the same mutation in his or her genes, and a method should be devised for cleaning and replacing these cells.

Another problem is the cost. It is reported that preparation of a series of multipotent cells will cost about one million dollars. However, the cost is expected to decrease and cells will be developed for the treatment of Parkinson’s disease, which is caused by a loss of neurotransmitter substance, which enable communication between nerves, and dopamine.

Treatment of macular degeneration is a popular target in this field. Patients gained the ability to read, though slowly, one year after the transplantation of part of stimulated multipotent cells to a damaged retina.

Such research studies normally cause some opposition. Playing with genes and embryos involve certain ethical and health risks. Yet, as reported in a Prophetic tradition, with all our God-given abilities like intelligence, curiosity, and willpower, humans can, and hopefully will, find cures for all diseases. Research into stem cells has the potential to provide many breakthroughs in these efforts to find healing for every human. Scientists and ethicists have to work together to determine our direction not to cause any unintended harm to any single soul while moving forward with this research.

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

The genera Escherichia is thought to have emerged around 102 million years ago and is known as a gram-negative pathogenic bacteria mostly found in the intestines of warm blooded animals [1]. German pediatrician and bacteriologist Theodor Escherich discovered E. coli in 1885, and for many years the bacterium was simply considered to be a commensal organism of the large intestine. It was not until 1935 that a strain of E. coli was shown to be the cause of an outbreak of diarrhea among infants [2]. The reason its pathogenic properties were discovered so late is that many of its strains are harmless. However, virulent strains of E. coli can cause various diseases in humans and in domestic animals, and are also sometimes responsible for product recalls due to contamination. Gastroenteritis, urinary tract infections, and neonatal meningitis are the most commonly observed diseases in humans, and in rare cases virulent strains are also responsible for haemolytic-uremic syndrome, peritonitis, mastitis, septicaemia and Gram-negative pneumonia [2]. Various outbreaks all around the world have been caused by E. coli, causing millions of deaths and sick people and billions of dollars have been spent fighting it. Even though death rates have decreased with the evolution of modern medicine and the discovery of antibiotics, the outbreaks are still a major concern for all countries, such as the recent outbreak in Germany in 2011 affecting 3,950 people and killing 53 [3].

Its reputation has not been one of great dignity, and it has ruined the reputation of many. You may recall in 1993, the fast food chain restaurant “Jack in the Box” suffered a major corporate crisis involving E. coli O157:H7 bacteria. Four children died of hemolytic uremic syndrome and 600 others were reported sick after eating undercooked patties contaminated with fecal material containing the bacteria at locations in Seattle and the Pacific Northwest, USA. The chain was faced with several lawsuits, each of which was quickly settled but left the chain nearly bankrupt and losing customers.

But don’t these creatures have any properties to be appreciated, I wonder…

Compared to eukaryotic cells, bacteria have a pretty basic mechanism of functioning. They don’t have sophisticated organelles, and they do not have a cell nucleus where their DNA is stored. Everything is floating along all together in the cell cytoplasm (which shocks me when I reflect upon how such a small and simple organism can cause such severe pain on “highly evolved modern humanity”). It has the basic metabolic tools for survival. And even though, at first sight, it is tempting to look down on its simplicity, today we know that it is this simplicity that gives us space for making many modifications and experiments on it, whereas in more complicated cells, like animal cells, the moment a modification is made, the entire system reacts to that and causes much trouble in the process.

The turning point of E.coli making a huge impact on our lives was in 1973, when Stanley Cohen and Herbert Boyer discovered the “Recombinant DNA Technology.” This technology allowed specific genes to be isolated from one organism and cloned to another organism by the help of bacterial plasmids. The first commercial product to be synthesized by this technology was human insulin, which is used for the treatment of diabetes [4]. This brought an amazing amount of recognition and appreciation for the technology, as the practical aspect of the technology was now proven to be commercially profitable. For the insulin to be produced, the DNA sequence that encodes human insulin was synthesized and transplanted into a plasmid that could be maintained in a non-pathogenic strain of E.coli [4]. Now the bacterial host cells acted as biological factories for the production of the two peptide chains of human insulin, which, after being combined, could be purified and used to treat diabetics who were allergic to the commercially available porcine (pig) insulin, or for diabetics from certain religious groups who abstain from pork products such as Muslims, Jews, some Christian groups, and many more who have similar concerns.

This was only the start of an incredible new technology which used bacteria to produce different proteins or enzymes to cure human diseases. Today more than 200 new drugs have been produced by recombinant DNA technology and have been used to treat over 300 million people for diseases such as cancer, multiple sclerosis, cystic fibrosis, and stroke, and to provide protection from other infectious diseases. Over 400 new drugs are in the process of being tested in human trials to treat such diseases as Alzheimer disease and heart disease (to name only two) [4].

Today E.coli is frequently used as a model organism for all kinds of microbiological experiments. In the lab, E. Coli. is one of the first micro-organisms that is thought of for testing a biological experiment. The reason is that E.coli cells are cheap to purchase and to sustain. They grow easily and rapidly in lab conditions and have non-pathogenic strains, so they are not dangerous for the researches doing the experiment. Whereas purchasing more complicated cells such as cancer cells or stem cells may be very costly, and moreover, may need special lab conditions to be sustained; so before more complicated cells are purchased, the experiments are usually tried out with E.coli or some other kind of model organism. More importantly, E. coli was one of the first organisms to have its genome sequenced; the complete genome of E. coli K12 was published by Science in 1997 [5]. Other areas in which modified E.coli has helped humanity are vaccine development, bioremediation (fighting pollution), and production of immobilised enzymes [6].

One specific example of the benefit of recombinant DNA technology for the environment is its use in the paper industry. Before the 1970’s, when there wasn’t much environmental awareness in the paper producing industry, poisonous chlorine compounds were conventionally used to achieve pulp brightness of a high order in the manufacture of high-quality paper products [7]. This chemical bleaching technique precipitated a tremendous environmental concern considering the magnitude of the industry. Plants treated with elemental chlorine produced significant amounts of dioxins. Dioxins are highly toxic, and their health effects on humans include reproductive, developmental, immune and hormonal problems. They are also known to be carcinogenic. Over 90% of human exposure is through food, primarily meat, dairy, fish and shellfish, as dioxins accumulate in the food chain in the fatty tissue of animals [7]. One alternative for these chemical bleaching processes is the use of the enzyme “xylanase,” which degrades the linear polysaccharide beta-1,4-xylan into xylose, thus breaking down hemicellulose, one of the major components of plant cell walls. Even though the use of xylanases in this industry has increased significantly with the discovery of Viikarri et al. (1986), the enzyme needs further improvements for it to be commercially acceptable [6]. To ensure the commercial utilization of hemicellulosic residues in the pulp and paper industries, the production of higher xylanase yields at low capital cost is required [6]. Such studies are ongoing with the purpose of partially mutating the amino acid sequence for the purpose of especially increasing the thermal stability of the enzyme and also increasing its metabolic activity. The gene mutation and gene expressions are generally done in either E.coli or yeast cells. Davoodi et al. has mutated the enzyme up to the point where the transition temperature increased 12 0C by introducing disulfate bonds in the enzyme [8]. The wonders this enzyme can do for the health of the environment is breathtaking, and is an area which should be further studied until finding the commercially viable kind that will eliminate chemicals from the paper industry during bleaching.

Even though some controversy remains on gene transferring, its tremendous positive impact on humanity cannot be denied. I personally think that it does need constraints and strict regulations, but this technique is one of the most remarkable techniques discovered in modern times, and E.coli has no doubt played a great role in the availability of this technology.

Even though condemning E.coli and stating its “evilness” seems like the most obvious path, we all ought to appreciate the variety and uniqueness of these creatures which also allow us to produce such large varieties of drugs. We ought to appreciate its simplicity, which allows it to have a chance of producing such sophistication. We ought to reflect upon the fact that something can be classified as “good” or “bad” only by the means in which we perceive it, and the reality of it may be completely opposite of what we had thought initially.

McPen is a freelance writer in natural sciences, Montana, US.

References

1. Battistuzzi FU, Feijao A, Hedges SB. 2004. “A genomic timescale of prokaryote evolution: insights into the origin of methanogenesis, phototrophy, and the colonization of land”. BMC Evol. Biol.
2. Todar, K. “Pathogenic E. coli”. Online Textbook of Bacteriology. University of Wisconsin–Madison Department of Bacteriology.
3. “German-grown food named likely culprit in deadly outbreak”. CNN. (5 June 2010).
4. Glick, Bernard, Jack Pasternak, and Cheryl Patten. 2010. “MOLECULAR BIOTECHNOLOGY Principles and Applications of Recombinant DNA . 4th Edition.” Washington,DC: ASM Press, pp. 3-13.
5. Blattner FR, Plunkett G, Bloch CA, Perna NT, Burland V, Riley M, Collado-Vides J, Glasner JD, Rode CK, Mayhew GF, Gregor J, Davis NW, Kirkpatrick HA, Goeden MA, Rose DJ, Mau B, Shao Y (September 1997). “The complete genome sequence of Escherichia coli K-12”. Science 277 (5331): 1453–62.
6. Cornelis P. 2000. “Expressing genes in different Escherichia coli compartments”. Curr. Opin. Biotechnol. 11 (5): 450–454.
7. Beg, Q.K., M. Kapoor, L. Mahajan, and G.S. Hoondal. 2001. “Microbial xylanases and their industrial applications: a review.” Springer.
8. Davoodi J., Wakarchuk W.W., Carey P.R., Surewicz W.K. 2007. “Mechanism of stabilization of Bacillus circulans xylanase upon the introduction of disulfide bonds.” Biophysical Chemistry, 125 (2-3) , pp. 453-461.

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.

Gómez-Valdés et al. Lack of Support for the Association between Facial Shape and Aggression: A Reappraisal Based on a Worldwide Population Genetics Perspective. PLoS ONE, 2013; 8 (1)

It is a common misconception that some people are profiled to be angry or aggressive because of their physical appearances, particularly their craniofacial shapes. In addition, there have been some studies suggesting that men with certain facial traits (round-shaped faces) are more likely to develop aggressive and unethical behavior. A new study using a sample of around 5000 individuals from 94 different countries has found no correlation between facial shape and aggressive/criminal behaviors. Researchers analyzed fWHRs (facial width-to-height ratio) and 2D/3D craniofacial landmark coordinates to estimate any possible correlation between skull shape and aggressive behaviors in men. First, they utilized the famous skull collection in Hallstatt/Austria to investigate any potential correlation between skull features and life history parameters of individuals, such as their overall fitness. Second, they analyzed the male prisoners convicted of crimes like inter-personal aggression (homicide, robbery etc.) from Mexico City Federal Penitentiary to see whether there is any relation between skull shape traits and aggressive crimes. Analyses of both databases have found no significant correlation between skull shape traits either with the fitness of males or with their aggressiveness. This study has very important social and political implications in today’s societies, as we unfortunately see many ethnical, racial and even physical prejudices. This comprehensive study has undoubtedly showed once more that physical traits cannot be a reliable predictor of complex human behaviors, which are mostly shaped by external factors such as education and socio-cultural practices.

Biggest Structure in the Universe Discovered

Clowe et al. A structure in the early Universe at z ∼ 1.3 that exceeds the homogeneity scale of the R-W concordance cosmology. Monthly Notices of the Royal Astronomical Society, January 11, 2013

Throughout history, mankind has been trying to answer the questions of “how big” or “how far,” when looking into the vast expanse of the universe. As new technologies are developed, bigger discoveries and consequently bigger numbers are brought to light. An international team of astronomers recently discovered a collection of 73 quasars which form a single structure; the largest structure ever observed in the entire universe. A quasar, short for quasi-stellar object, is the luminous center of a galaxy that surrounds a super massive black hole. The distance of these newly large quasar groups to the earth is about 9 billion light years (1 light year is approximately 9.5 trillion kilometers). The size of these structures is simply mind-blowing. Even if we have a spacecraft that travels at the speed of light, it would still take about 4 billion years to cross. If we put this overwhelming size into perspective, the Milky Way—earth’s home galaxy—is only about 100,000 light-years wide and our neighbor galaxy Andromeda is only 2.5 million light-years away from the Milky Way. So these quasars are 1600 times larger than the distance from the Milky Way to Andromeda. This discovery seriously challenges the size calculations based on the widely accepted Cosmological Principle which assumes that the universe is essentially homogeneous when viewed at a sufficiently large scale. Cosmological Principle predicts that there should not be any structure in the universe larger than 1.2 billion light-years. A four billion light-years wide structure would obviously be an outlier when compared to other structures in the universe and it might contradict with the homogeneity of the universe. However, scientists think that such contradiction would not necessarily falsify the Cosmological Principle originally established by Albert Einstein. It might only change the assumptions of the theory that define at which scale the universe can sufficiently be viewed.

More Twists on Double Helix

Biffi et al. Quantitative visualization of DNA G-quadruplex structures in human cells. Nature Chemistry, 20 January 2013.

About 60 years ago, on April 25th 1953, James Watson and Francis Crick published a one-page paper where they described the “double helix” structure of the DNA, the molecule that carries genetic information from parent to offspring. This discovery not only revolutionized the biological sciences and medicine but also dramatically changed the way we perceive life, nature and most importantly ourselves. Yet, new findings on DNA structure keep surprising us. Scientists from Cambridge University discovered the first quadruple helix—a four-stranded DNA structure in human cells which they named “G-quadruplex.” These structures were previously observed in test tubes but they were never found in cells. The building blocks of DNA molecules consist of four different bases: Adenine (A), Guanine (G), Cytosine (C) and Thymine (T). G-quadruplexes (G stands for Guanine) are formed by four guanine bases that forms a square DNA helix. Researchers found that these structures are enriched in rapidly-dividing cancer cells, specifically at the ends of chromosomes called telomeres. When researchers targeted and trapped these quadruple DNA structures with synthetic molecules, they found that DNA replication slows down and cell division is blocked. Researchers suspect that these quadruple DNA structures in telomeres of cancer cells could explain why cancer cells rapidly proliferate and divide. It is still not clear whether G-quadruplexes exist in healthy cells but targeting these structures in cancerous cells with pharmacology seems to be a promising method to stop the spread of cancer.

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