It is estimated that there are approximately 100 trillion cells in the human body. They fulfill their duties harmoniously with all the systems, organs, and tissues manifesting innumerable signs of wonder and wisdom. If a disruption occurs to the working of cells or the coordination among cells, the process leading to cancer starts to develop in the body’s tissue.

The recent increase in cancer occurrences has led researchers to look into its development. The phrase “cellular anarchy” is sometimes used to refer to cancer’s development. Indeed, when we examine the mechanism of cancer development, we see that cells engage in irregular – anarchic – activities in addition to regular ones.

Abnormalities emerge in cancerous cells during cell division and differentiation (when they transform into specialized cells according to different tissues). Cancer cells divide uncontrollably. Under normal circumstances, numerous genes are active in cell division. In cancerous cells, however, failures occur in the mechanisms that control division. Moreover, due to differentiation flaws in cancerous cells, undifferentiated cells, which fail to acquire features that enable them to function in a tissue or organ, form groups of cells that constrain and damage other cells because of the space they occupy.

Checkpoints in cell division and tumor suppressing genes

How is cell division controlled in a normal cell?

Our cells go through numerous stages as they divide. The beginning of each stage is called a “checkpoint” because it is where errors in cell divisions are checked. At each checkpoint (called G1, S and G2) are proteins with certain duties. One of these proteins, P53, suppresses development of cancer. In other words, P53’s job is to prevent failures during cell division, hence blocking the path to cancer’s development in the cell. Whether there is a flaw in the DNA it is checked over and over again at each checkpoint. If no error is identified, the next stage proceeds. In this way, it is ensured that there is not any genetic error in the cells formed as a result of division. If there is an error, cell division is stopped. First an attempt is made to correct this genetic error. If it can be corrected, cell division is resumed. If the error is too big to be corrected, then the cell is scheduled to die; this is called apoptosis. It is worth remembering at this point that proteins that are too minute to be observed even by microscopes are tasked to perform these stupendous mechanisms. It is remarkable that they were designed to work so effectively.

Because these systems are disrupted during the development of cancer, genetically flawed cells form and multiply. Proteins produced with the genetic codes of the flawed cells are also flawed, and these flawed proteins cause a failure of the mechanisms that constrain cell division. Unconstrained cells have an abnormal capacity for division and they divide continuously, which is why cancerous cells have a greater ability to divide than normal cells.

Proto-oncogenes and oncogenes

It is essential that the parts of our body that grow, develop, or get damaged be repaired. In such cases, our cells synthesize certain “signal” molecules which are responsible for carrying to the nucleus the information that our cells should divide. As a result of the incoming information, some DNA regions called proto-oncogenes are stimulated and cell division gets underway. Proto-oncogenes are genes responsible for checking the start of cell division. When the human body encounters various cancer-making elements, damages occur in proto-oncogenes, which transform into oncogenes, or genes with the potential to cause cancer. Oncogenes lead a cell to develop cancer because cell division does not stop where it should and continues endlessly in the absence of healthy proto-oncogenes. Underlying abnormal tissue growth and spread to other organs is the fact that the control over cell division is lost.

Genetic treatment of cancer

It became apparent that age-old treatment methods proved wrong once it was discovered that the biological foundations of cancer stemmed from genetic disruptions. Despite its increase in the last century, cancer has in fact been seen throughout the history of mankind; even ancient Egyptian papyri talked about it. Because there was not a definite treatment for cancer, radical treatments were used, such as burning or cauterizing the tumor. In the first half of the twentieth century, only surgical methods were implemented in cancer treatments. Desired results could not be obtained by surgical procedures, which ended up with the excision of entire organs.

Research studies were launched in the second half of the twentieth century into whether it was possible to treat cancer using drugs. These studies revealed that cancer stemmed from genetic flaws (like the ones in oncogenes and tumor suppressing genes), which led to questions about types of treatment. Treatments of flaws at the genetic level are based on genes themselves. These treatments use such methods as stopping genes that work abnormally, eliminating the products of these genes, and killing cancer cells by making use of their genetic mechanisms.

New incidents of cancer are likely to continue to develop, for people are exposed to factors that cause disruptions of the makeup of genes. To prevent cancer, it is critically important that one should have a conscious, natural, and balanced lifestyle. People should be well-informed about the effects of smoking, genetically modified food, radiation, stress, and chemicals, so that they can lessen exposure to such risk factors. Moreover, more frequent implementation of screening tests will make early diagnosis easier. More effective methods with fewer adverse effects should also be developed for higher success rates in cancer treatment. Genetic treatment of cancer is a relatively new field but an increasing number of studies focus on it. These studies aim to kill only cancerous cells and spare healthy ones. It can be expected that research into this field will produce promising outcomes in coming years.

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.

Astronomers have discovered a planet with the longest known orbital period. Exoplanet Kepler-421b has been identified through the Kepler observatory, a space-based telescope. It circles its star once every 704 days. More than 1800 exoplanets have been discovered so far, but compared to Kepler-421b, those had much shorter orbital periods, like a few weeks or even a few days. The host star for Kepler-421b is much like the sun, but it is little bit smaller and relatively cooler. With an orbital distance of 177 million kilometers, Kepler-421b gets about one-fourth the light from the host star as the Earth receives from the sun, which makes the exoplanet as cold as -100 °C. The unusual orbit places Kepler-421b beyond the “snow line,” which is accepted as the dividing line between rocky and gaseous planets. Outside of the snow line, water condenses into ice grains that stick together to build planets known as “gas giants.” Since gas giant planets are very close to their stars, theorists believe that many exoplanets migrate inward early in their history. However, Kepler-421b is the first example of why such migration may not be necessary.

Sunflowers’ internal clock

Plants are known to grow toward the sun to maximize the amount of energy they absorb. Sunflowers (Helianthus annuus) show the most fascinating behavior during summer, when they follow the sun as it rises in the east every morning and sets in the west every evening. In a recent study, scientists challenged the obvious explanation for this plant’s behavior: are flowers solely responding to sunlight or are there other unknown mechanisms at work? They designed a clever yet simple experiment where they grew sunflowers in chambers with a fixed overhead light that was continuously on. Surprisingly, for several days, the sunflowers under constant light kept moving as if the sun were rising in the east and setting in the west. This unexpected result suggests that sunflowers were not responding only to the direction of the light but also to an internal biological clock. Furthermore, they discovered that sunflowers bend when one side of the stem grows faster than the other. For example, the west side of the stem seems to grow faster to bend the plant towards the east in the morning. Scientists now hope to understand how an internal biological clock in sunflowers has the opposite effects on opposite sides of the stem. Sunflowers are not the only plants performing this diurnal dance; other agriculturally important crops such as soybeans and cotton exhibit the very same behavior. Solar tracking is known to boost plant yield and discovering the mechanisms of how plants track the sunlight might have important implications for improving global agricultural yields.

Friends linked by genes

It is a common observation that close friends look alike. Even centuries ago, Plato noted the tendency that good friends usually have similar appearances. Recently, a group of geneticists took this idea even further and suggest that people on average tend to choose friends who are genetically similar. The study provided convincing evidence that we have more DNA sequences in common with the people we pick as friends than we do with strangers in the same population. Researchers performed a genome-wide analysis of approximately 1.5 million markers of gene variations from 1,932 subjects of the Framingham Heart Study, which is one of the most comprehensive genetic databases. They identified 1300 pairs of non-relative friends and compared their genetic information to each other. The analyses showed that friends share similar genetic variations (around 1% genomewide), to the degree that it is as if they have the same great-great-great-grandparent – in other words, as if they were fourth cousins. Notably, friend pairs seem to have the greatest similarity in the genes that are responsible for a sense of smell and they show the most difference in immunity-related genes. Friendship entails spending a lot of time together and looking out for each other. Odors are strong behavioral cues in human psychology and people with similar olfactory preferences might like to prefer living or hanging out in similar environments. Likewise, it is potentially a big advantage that friends don’t get infected from the same microbes at the same times, so that one of them can take care of the other. As much as these anthropological implications are merely speculations with many caveats – and despite there being many obvious social, ethnical, and cultural factors that help determine friendships – the genetic basis of friendship and other social interactions may hold answers to at least some of the mysteries of human behavior.

Loneliness is a serious public health concern, akin to both obesity and smoking. Why is it not treated as such? Through faith, we can combat this growing crisis.

Loneliness is a state when people are unable to share their inner world with anyone around them. It is very natural that a person desires to be alone from time to time. When this is a short term desire, it can be a means of acquiring harmony with life; however when it becomes chronic, it is harmful for human health. Therefore, solitude is like a sword which has two sharp sides. Solitude in itself is not good or bad; rather the period and severity of it defines if it is good or bad. The severity of loneliness is not measured by how many people that individual has in their social environment; it is measured by how the individual feels in his inner world. In modern societies, loneliness is an important topic of multidisciplinary research, especially in our times due to overuse of social media, as “loneliness” is quickly becoming endemic, threatening our public and individual health.

One of the leading factors behind the increase of loneliness is the spread of immigration, which suddenly tears people from their original cultures and from their families. With the social bonds weakened or broken, loneliness is more severely and increasingly felt. For example according to the 2006 records, 29 million people in the US, a predominantly immigrant nation, were living alone. When compared to the records from 1980, this means a 30% increase in the number of people living alone. Another shocking number is that while 10% of people said they wouldn’t share their personal matters or trust with another person in 1985, this number increased to 25% in 2004.

In our times, loneliness and isolation have become as risky as smoking and obesity. The latest research in neurobiology and clinical research has shown that chronic loneliness has negative effects on the heart, and the immune and nervous systems. Contraction and resistance are much higher in the veins of people experiencing chronic loneliness. Blood pressure rises with the arteries narrowed and shrunk. This makes the heart beat abnormally faster, and this results in the corrosion and laceration of the capillaries. According to epidemiological studies, people who feel alone tend to have shorter life spans and illnesses such as heart disease and depression are at higher risk. They’ve also proven that people socially isolated or feeling lonely are more likely to catch a viral infection.

Studies have shown that, an individual can still feel lonely even though the number of people around them is high. Their social environment, statue, reputation, and property are only of formal assistance and they do not directly prevent an individual from feeling alone. Spiritual loneliness can exacerbate this feeling. Without a deep spiritual life to seek comfort in, they can fall further into depression when faced with problems.

Genetic thermostat and activation of loneliness

There are parts of the human brain which almost work as a thermostat and activate loneliness. Since the information for these parts of the brain are encoded in our genes they are called the genetic thermostat. This genetic thermostat, which we have inherited from our parents, has the duty to adjust the time of response we give to a trigger. Socio-cultural factors and genetic inheritance are assigned to determine the thermostat’s intensity and period of operation. These principles are mostly shaped in childhood and determine the threshold and intensity of the loneliness that is felt later on. In other words, the pain and suffering caused by loneliness depends on the genetic thermostat of the individual. In some genetic structures, the activation settings of the thermostat are low; and in some they are high. Therefore, the feeling of loneliness resulting from social isolation triggers a different response in every person. Even though clinical loneliness does depend on genetics to some extent, it is a curable. Around half of the factors that are behind feeling lonely depend on genes. A study about loneliness conducted on 8,683 twins showed that genetic treatments are 37% effective in treating this feeling. In summary, a departure from our social environment makes us go through different levels of pain depending on our genetic thermostat. Therefore, loneliness is felt in different forms in different natures.

The biological consequences of loneliness

Our body gives out different messages through pain and suffering. In the same way pain and suffering gives us messages of something going wrong in our body, extreme loneliness also has effects on the body, alerting us of something going wrong. Anxiety and physiological changes in our body give out alarming signals when our relationships weaken. These signals warn us that we have to change our attitude and actions in a way that will strengthen our relationships.

It has been observed that stress molecules (cortisol in saliva, adrenalin in urine) increase significantly in people who go through deep phases of loneliness. It was also observed that the body’s sympathetic nervous system, which is responsible for a “fight and escape” response, increased these activities, too. In people who are lonelier, the amygdala is triggered; this further heightens a person feeling of risk. These people are constantly on edge, their “flight” response activated. Therefore, people going through chronic loneliness have very low sleep quality. They wake up tired or even exhausted. They take less pleasure from activities that give rest and bring joy to other people. The degree of their satisfaction and happiness is low. They start losing the joy of living.

Another area of the body affected is the ventral striatum area, which is the award mechanism activated by factors such as food or money, as well as social feelings like sympathy. In a study conducted at the University of Chicago, the activity of the ventral striatum in 23 female university students feeling deep loneliness was measured with magnetic resonance scanning. The study showed that when these females were shown pictures of laughing and happy people, there was a significant decrease in their award mechanism compared to a normal person. So the deep feeling of loneliness locks the award mechanism of the brain, preventing the person from taking pleasure from life, thus leading the person to anxiety and sorrow.

Deep loneliness also affects the activity of the prefrontal cortex of the brain. This is the area of willpower; it brings a limit to activities triggered by instincts, such as eating or drinking. Field studies and surveys have shown that people feeling deep loneliness are more likely to have an unhealthy diet, increase their consumption of alcohol, and live a passive life style without exercising. Moreover, in the management control conducted in labs and that require prefrontal cortex activation, lonely people show little success. The prefrontal areas of these people do not respond fast enough, leading them to little success in these experiments.

Lonely people are more emotionally unbalanced when faced with stress. They find it very hard to control their emotions. They are more sensitive to negative hints when they are among people. They tend to interpret social interactions negatively rather than positively. In one study, the words that address the emotional state of a person were flashed on a computer screen with different colors. Later on, the colors of these words were asked to people feeling deep loneliness and to people who did not feel lonely. People feeling deep loneliness gave delayed answers about the colors of words such as “isolation, rejection, exclusion.” The people who did not feel lonely showed no such delay. This experiment shows that the human brain was created to give alarm signals in case of deep loneliness.

Social bonds and interactions enable a person to be open and accessible to other people. To make this openness and accessibility beneficial is both easy and difficult, simple and complex. People go through periods of wanting to be alone – with themselves or with God – just as they go through periods of desiring more social contact. A healthy person moves freely from state to state. To discover and control this oscillation between the two needs is to learn the best way to manage our lives.

How can deep loneliness be cured?

Since social isolation and loneliness affect people differently, a person should know the nature of his genetic thermostat and should make an effort to stay at his individual comfort zone. Every person has zones or intervals where they feel comfortable expressing their emotions, ideas and attitudes. Similarly, every person has different zones and thresholds for loneliness. Every person needs to understand their limits. Just as our fingerprints are unique, so, too, is the amount of solitude we need.

For those already suffering from loneliness, one of the best cures is a change in point of view. In other words, loneliness is cured by changing the person’s focus from the negative to the positive. People lead better lives when they adhere to the maxim, “Those who attend to the good side of everything contemplate the good. Those who contemplate the good enjoy life” (Nursi, The Letters, Epigrams – Seeds of Truth). People who understand and practice this in their lives have obtained the key to happiness.

A deep, personal relationship with faith is also a major cure for loneliness. Friends and earthly occupations only give comfort to a person until the grave. If the person who is isolated has very solid spirituality, and has acknowledged God as his real friend, he never undergoes a feeling of loneliness that would otherwise destroy his health. With faith and hope, the dungeon of loneliness becomes a school of imprisoned Prophet Joseph. Faith reminds him: “If you want a friend, God is sufficient. Indeed, if He is a friend to you, so is everything. If He is pleased with you, even if the whole world is displeased, it is of no consequence” (Nursi 23rd Letter, 21st Gleam). Sorrow, grief, sadness will not stop by you. Even if they do stop by you, they are bearable since they come from Him. They turn into worship by activated patience. Through faith, a person can achieve fulfillment in both this world and the next.

References

• Miller, G. 2011. “Why Loneliness Is Hazardous to Your Health.” Science. Vol. 331. 14 January, pp. 18-140. www.sciencemag.org
• Cacioppo, J. T. and Patrick W. 2008. Loneliness: Human Nature and the Need for Social Connection. W.W Norton Company. New York.

If we consider human nature as a book, the encoded information contained within, together with all the elements of inner and outer environments (bio-psycho-socio-cultural), becomes meaningful and functional. This is because each book has a visible structure composed of letters (semiotic DNA sequence) and a manifested meaning (semantic web) in a particular environment. From this point of view, genes should not be seen as mandatory codes, but should be considered as similar to the art of marbling (or ebru, which is the making of different patterns on a fluid by small vibrations of the ink droplets), for they are created by the united effect of various dynamic forces, and can only be understood accordingly. Human willpower and responsibility will also gain meaning and value when they are analyzed within the framework of the reaction intervals presented within the motifs of human nature which are shaped by the mutual effects genes and cultural factors have on each other. In this sense, human nature and culture should be evaluated together. We can organize the factors that determine human behavior and manners under three main titles – genetic, physicochemical environment, and psycho-socio-cultural factors. We can only speculate statistically as to how large or small a role each factor plays in development.

Behaviors like an inclination to crime, having intimate feelings for same sex individuals, cognitive and sensory sharpness, a desire for excitement and risk, or an inclination to addiction cannot be described by one or two genes. For instance, there are many factors (environment, genes) involved in acts of violence. However, one missing and insufficient factor can trigger violence. For instance, the Monoamine oxidase A enzyme is encoded by the MAO-A gene; this enzyme is in charge of degrading neurotransmitter molecules such as dopamine, serotonin, norepinephrine (these enable signaling between nerve cells). Depending on the mutations or polymorphisms of this gene, if the enzyme cannot function sufficiently, these individuals display an inclination towards violence and aggressive behavior. But if the person is aware of the situation and gets educational support from others, this behavior can be controlled.

Similarly, every person has a variable degree of genes that put them at risk for cancer. If these genes are activated via environmental factors – such as smoking, poor nutrition, mutagens, carcinogens – cancer may develop. On the other hand, if a person is lacking the cancer-causing genes or has low inclination towards cancer, such a person may not get cancer, even if he or she is a smoker. Similar statements can be made for genes associated with addictions, sexual perversions, and violent tendencies. More significantly, we can produce more value and meaning out of behavior-related genes when we evaluate them according to their context, position, and other factors, along with their relations to other genes. That is to say, there is a complicated network of factors that shape behavior. That’s why a DNA sequence alone cannot determine, all by itself, the development of emotions and manners, skills, and personality. In other words, phenotype can never be predicted 100% just by the interpretation of genetic information.

Brain and personality development is a multi-faceted, exposome mystery. From the start of pregnancy, especially throughout the preschool era, everything one is exposed to, and the way those events shape one’s nature, is called exposome. This can include subconscious events, for all sorts of personal history plays a role in such development. The connections of 1011 neuron cells that exist in an average human brain are not only determined by genes. Human DNA contains 6.2 x 109 nucleotide (letter), or information. Reading and using this raw information depends on many factors. Neurons can establish new connections via internal and external stimuli, while on the other hand, the number of neuron cells and connection networks can be changed by the neurochemical substances and hormones that they synthesize. All of the information required to define fine details in the motifs and connections of brain cells is not present in the genome. Mere environmental factors are not enough to complement this missing information.

Aside from these, many factors play a role in brain development and function. When the ends of axons and dendrites extend, they do so by recognizing nanomolecules that guide them all the way to the target organ or region. They happen to make minor changes and deviations during this extension. These changes are extreme enough that this extension is part deterministic and part trial and error. They reach the target through a statistically systemic algorithm but with a certainty less than 100%. Axons that are extended from eyes to the brain have a 1% possibility of taking a wrong turn at optic chiasm, and therefore not reaching the brain or arriving at the wrong region of it. However, there are also signalization systems built in our brains that recognize and correct these errors. If axons cannot receive the correct signals from target neurons, they get degraded. And sometimes a neuron of the axon terminates itself. These observations clearly show that brain development does not take place by a molecular program that is predetermined down to the minutest details but rather through a flexible program open to changes and errors.

This flexible program is explained by materialistic philosophy as “chance,” which basically means being in the right place at the right time to encounter the right factors. The same program, in religious literature, is explained by factors known as fate, kismet, destiny, divine blessing, and grant. Aside from that, there are also certain uncontrollable activations and a genetic background in the brain that are involved before we start a conscious action. From this perspective, motifs generated by biological and genetic inclinations set the infrastructure for the freedom of decision making and self-determination. Since our thoughts, emotions, and acts are formed within the neurogenetic and neurochemical construct of the brain, the motif that is created by the background here generates inclinations for specific acts and behaviors. In other words, events that take place in our brain chemistry during the fetal period and early childhood years are significant determinants of human development. The human brain can function in a state with willpower and consciousness, but can also function automatically, without consciousness. Briefly, it is through our genes that the framework of what we can achieve, our reaction intervals and threshold values are determined, and the possibility of an act is indicated. But the boundaries of the final decision are determined via statistical possibilities as a result of a person’s interaction with their environment. Therefore the boundary is not determined in a mandatory fashion, but via external dynamics (like manners, beliefs, or moral nourishment).

Human willpower is our capacity and strength to make free decisions and selections under the effects of spiritual, genetic, and environmental frameworks (endophenotype). The decisions and selections cannot take place independently from the sources nourishing one’s metaphysical world, cultural circles, or from the impact of neurochemicals in the brain and our hormones. “God burdens no soul except within its capacity” (2:286) is a sign of mercy and compassion from the Qur’an, indicating that the field of action and boundaries of the human willpower are determined based on multiple factors and wise causes. Producing customized religious rulings according to one’s natural strengths and weaknesses is also a very meaningful legal action in Islamic law. It is, in a sense, an acknowledgement that everyone has trials and experiences that are different than others’.

Humans have responsibilities within defined, limited conditions, and they can only make decisions within those permissible intervals of conditions and the constraints of their natural dispositions. If we can analyze human actions in a model that looks into their dispositions, cultural environments, genetic inclinations, and spiritual and moral nourishment, then we can attain better results in the education and character development of human beings.

Each factor mentioned above affects the child’s sexual separation and differentiation to various degrees. Misbehaviors during sexual development may emerge as a result of a complex mosaic of biological, psychological, sociocultural factors. There is not a complete consensus around the main reasons for this, yet each researcher favors one factor in the light of their expertise and ideological choices. However, objective observations and research point out that the quality of relationship between the parents and children is very influential in this matter. The display of unhealthy sexual inclinations stems from a negative background where there is not enough parent-child relationships to help the child develop. In families of children with strange sexual behaviors, a suppressive, excessively controlling model of mother and a distant, aggressive model of a father who resorts to violence are often found to exist. That is why many problems with intimacy and sex that occur later in life can be viewed as a developmental ailment and a problem of insufficient parental communication rather than a mandatory genetic phenomenon.

Various problems can arise when healthy differentiation and separation do not take place during a child’s development. A child, in the beginning, is like a part of the mother. If differentiated by detachment from the mother, and from her compassion and care, a child struggles to develop a healthy sense of ego. Such a child becomes inclined to develop a personality that is dependent, passive, and lacking sufficient confidence.

Research clearly states that each child is born with different inclinations and threshold values that are determined genetically and hormonally for each of his or her possible characters and behaviors. These potential inclinations and threshold values can surface depending on internal and external stimuli and educational styles. Even though both genders carry hormones belonging to each other naturally, during development one steps forward upon expression of encoded gender genes. When it comes to displaying sexual abnormalities, everybody is, genetically speaking, a dry log or a wet log. A dry log can easily catch fire, a wet one does not. However, it is the responsibility of society and parents to provide a spark-free environment for the dry log. Spiritual and biological nourishment during the developmental process are found to be significantly influential in diseases and aging, in disorders of character development, and in anomalies in sexual behaviors. When proper measures are taken timely, via suitable environments and educational modes, the possible surfacing of behavioral pathologies may be prevented or reduced for children potentially at risk. Through correct guidance and education, the expression and regulation of genes can be altered and managed, controlling these naturally present inclinations.

Cezmi Aydin is a freelance writer in natural sciences.

References

• Alper, Joseph S. (1998). “Genes, free will, and criminal responsibility.” Soc. Sci. Med. Vol. 46, No. 12, pp. 1599 1611
• Meyer, Lia Midori Nascimento, Gilberto Cafezeiro Bomfim, Charbel Nino El-Hani. 2011. “How to Understand the Gene in the Twenty-First Century?” Sci & Educ. DOI 10.1007/s11191-011-9390-z
• Levitt, Mairi and Neil Manson. 2007. “My Genes Made Me Do It? The Implications of Behavioural Genetics for Responsibility and Blame.” Health Care Anal. 15, pp. 33–40.
• Richardson, Brian. 2011. “What’s wrong with me? Coming to terms with same sex attraction.” Nursing Children 24 and Young People. October 2011. Volume 23. Number 8. pp. 22-24.
• William J. Jenkins. 2010. “Can Anyone Tell Me Why I’m Gay? What Research Suggests Regarding The Origins of Sexual Orientation.” North American Journal of Psychology, 2010, Vol. 12, No. 2. pp. 279-296.
• Botz-Bornstein, Thorsten. 2010. “Genes, memes, and the Chinese concept of wen: toward a nature/culture model of genetics.” Philosophy East & West Vol. 60, No. 2. April 2010. University of Hawaii Press, pp. 167–186.

Original Article: Mak, G.K. & Weiss, S., Nature Neuroscience 13, 753 (2010).

Motherhood or maternal recognition is well characterized by associated brain plasticity during both early development and adulthood. Unlike motherhood, paternal-offspring recognition and its related brain plasticity is poorly understood. A group from University of Calgary designed a set of experiments to test whether father mice can recognize their own infants once they’ve reached adulthood. They exposed adult males to their own and genetically unrelated infants for 2 days. The fathers were tested for adult offspring recognition six weeks later. Assay compared the time spent by the fathers with their own and unrelated offsprings. Results showed that although the father mice show similar parenting behavior toward both sets of infants (own and adopted), they only recognize their own pups as adults. Paternal recognition is associated with increased prolactin (a hormone primarily associated to lactation), mediated neurogenesis in the olfactory bulb, and hippocampus, a major component of mammalian brain. These newly generated neurons are important for the formation of socially relevant olfactory memories. Authors also found that the fathers must physically interact with the infants in order to recognize them later. This is confirmed by some control experiments in which fathers are only allowed to see, smell or hear infants through a wire mesh barrier which was not sufficient to induce neurogenesis. One of the socially relevant benefits of paternal recognition of the infants as adults is to avoid incest interactions which cause inbreeding depression.

2- Recently revealed hideous effects of smoking on children

Original Articles: Brion, M.J. et al., Pediatrics 126, e57 (2010) & Kwok, M.K. et al., Pediatrics 126, e46 (2010).

Smoking is bad for our health, but apparently it may also have subtle, yet far-reaching consequences on our children according to two recent studies. The first study reports that mothers who smoke during pregnancy are more likely to have children with psychological problems. A related study presents evidence that babies who develop in the presence of second-hand smoke (from their fathers) may develop weight problems. Dr. Mary-Jo Brion of the University of Bristol tells “Babies exposed to smoke (in the womb) may be prone to rule breaking, such as lying, cheating, bullying, and disobedience in later years” and adds “To some extent it is somewhat surprising that … maternal smoking may also directly impact child behaviors from exposing the fetus to tobacco in utero.” The other study suggests that smoking around expecting mothers (even when the mother herself is not smoking) also affects the child: higher childhood weight appears to be clearly correlated with paternal smoking. “To protect their children, fathers should avoid smoking from conception onward,” says Dr. Mary Schooling of the University of Hong Kong. Furthermore, smoking mothers should not be too surprised to see their children “disobey” when they tell them not to smoke.

3- Exposure to certain wavelengths of light resets the body clock

Original Article: Gooley, J.J. et al., Science Translational Medicine 2, 31ra33 (2010).

With the introduction of high-tech gadgets into our lives, our daily functions have changed drastically. As opposed to old-fashioned bed-time reading of an “actual” book made of paper, we fiddle with our iphones or ipads or notebooks or channel surf on our bedside TVs before going to sleep. A recent study revealed that exposure to certain wavelengths of light, such as those from laptops or TVs, would negatively influence our circadian rhythms (daily rhythmic activity cycle) by resetting our body clocks (e.g., keeping us awake when we should be sleeping). The feeling of sleepiness at night time is triggered by the secretion of a hormone called melatonin. It had been known that exposure of blue light to the eye’s photoreceptor system located in the ganglion cells suppresses the melatonin secretion, therefore stimulating alertness. In their recent work, researchers at Brigham and Women’s Hospital showed that green light exposure of a different cell population on the eyes – cone cells – also resets the body clock by suppressing melatonin secretion. The senior author of the paper, Dr. Steven Lockley, said in an interview that “we need to think about the entire spectrum of light when designing light therapy or lightning designs to boost alertness or induce sleepiness.” The moral of the story is to be more vigilant about our interaction with fancy electronic gadgets at night if we want to have a healthy and relaxing sleep.

4- Poor teachers may impede good students

Original Articles: Taylor, J. et al., Science 328, 512 (2010).

Scholars know that educational environment, including both tasks and the social environment of a classroom, affects children’s achievement just as much as genetic factors. But the teacher plays a main role, because the quality of the educational environment depends on teachers’ performances. A new study underlined the importance of qualified teachers and how they can make a difference in education. The researchers examined the influence of teacher quality by studying 280 identical and 526 fraternal twin pairs in the first and second grades in different Florida schools representing a diverse environment. Identical twins share 100 percent of their genes and fraternal twins share half, and some of the twins were taught by the same teacher but some were in different classes. The researchers used an Oral Reading Fluency test which is based on how many words in a paragraph a child can accurately read in a minute in order to assess the reading skills of children. The researchers recorded the reading scores of students in the beginning of the semester and at the end of the semester, and they followed the students’ improvements during the year. To measure teacher quality, they used the scores of twins’ classmates. By studying twins’ groups, researchers were able to eliminate some other factors such as genetics and socio-economic conditions. According to the findings, the teachers played a role in “moderating” students’ achievements, and they helped the students to grow to their full potential. When teacher quality is very low, genetic variance is constricted, whereas, when teacher quality is very high, genetic variance blooms. As the study’s lead author, Jeanette Taylor, said “Better teachers provide an environment that allows children to reach their potential.”

Almost all of us are familiar with the fact that our bodily organs are composed of tissues, which are made of cells. The perfect machinery of the cells is controlled by our genes; i.e. DNA and RNA. Therefore, a minor defect or mutation in the genetic code may affect either partial or entire systems within the body. Some of these genetic diseases are inherited from our parents or relatives. Others may be introduced into our body through environmental mutagens, such as ionizing radiation, ultraviolet rays, or different chemicals within our food and drink; these can result in cancer or cardiovascular diseases. We can protect ourselves from the latter by using appropriate outfits, taking care with our diet, etc. However, inherited genetic disorders are usually unavoidable and sometimes have fatal consequences. Modern medicine is striving to find a way to treat these diseases. Although there are some medical procedures that may lessen the pain of patients or extend their life expectancy, there is no available comprehensive curative therapy for genetic disorders.

Gene therapy has become one of the rising stars in the field of molecular medicine during the last decade, with more than 1500 proposed or ongoing clinical trials worldwide. Gene therapy promises to provide curative therapies for a large number of inherited or acquired diseases, such as monogenic disorders, cancer, or cardiovascular disease. Gene therapy is universally defined as the replacement of an abnormal/dysfunctional gene in the cells of an individual with its correct and functional version. Mechanics use a number of tools to fix our cars for us when they give us trouble; in the same way, gene therapy can be used by doctors to alleviate or completely eradicate some diseases from our bodies.

Gene therapy is classified into two categories based on the target cells that are to be treated. The transduction of the differentiated cells of an individual, i.e. the somatic cells, is known as somatic gene therapy; the transduction of reproductive cells, i.e. gametes (sperm or ova), is known as germ-line gene therapy. Currently, there are many regulations in place that limit the likelihood of the modification of the germline in any gene therapy approach. This is because fear exists that the ability to alter the germline will result in the widespread application of gene therapy to achieve eugenic genetic enhancements, such as improvement of intelligence or physical characteristics. On the other hand, transgenic animals, which are used to detect the function of the genes within an organism, can be generated by modifying the germ-line. Furthermore, gene therapy is also classified into two groups: adult and fetal (in utero) gene therapy, according to the individual to be treated. There are several advantages and disadvantages to these methods, such as immune response, the pooling of mitotic cells, the amount of vector that is required, etc.; however, these are matters for a different article.

Gene therapy is achieved by using special exogenous genetic material transfer agents which are called vectors; these can be compared to the special tools used by auto mechanics. Over the years, a number of gene transfer vehicles, i.e. vectors, have been developed and these can be divided into two principal categories: non-viral (synthetic) and viral (virus-based) gene delivery systems.

Non-viral gene transfer can be achieved by using both physical and chemical methods. The physical methods include: i) Electroporation, in which areas of the cell membrane break down as result of an applied electric pulse, thus allowing DNA to enter the cell, ii) Ballistic gene transfer (the Gene Gun), which bombards particles coated with DNA into the cells, and iii) Microinjection, in which DNA is transferred through microcapillaries into the cells [1]. In terms of chemical gene transfer, lipofection is the most promising method; in this method negatively-charged DNA molecules bind to cationic lipid particles through electrostatic interaction and the DNA–lipid complex enters the cell through endocytosis/pinocytosis. Although these non-viral delivery systems exhibit low toxicity and can be easily produced in high concentrations on a commercial scale, in general, gene transfer using these agents is inefficient and often transient. Therefore, as a result of the viral vectors’ ability to efficiently deliver and integrate genes into the host genome, they are being engineered extensively to achieve a sustained and high-level expression of the gene of interest (transgene).

Viral vectors

Have you ever thought that one of the major pathological agents that cause catastrophic and even fatal diseases could be used to treat the same or a similar disease?

Viruses are equipped with specialized molecular mechanisms that allow them to efficiently transport the genomes into the cells they infect and use the cell’s machinery for their own reproduction. Molecular biologists first harnessed this machinery of transduction in the 1970s. Paul Berg used a modified SV40 virus containing DNA from the bacteriophage lambda to infect monkey kidney cells that were being maintained in culture. Viral delivery systems are based on replicating viruses that have the ability to deliver genetic information into the host cell, a process known as transduction [2]. Due to the fact that there are several advantages to viral vectors, these are the vehicles being employed in approximately 75% of all ongoing clinical trials worldwide. Numerous viruses are being used as the basis for the vectors, including, but not limited to, adenovirus (24%, n=377), retrovirus (20.9%, n=329), adeno-associated virus (4.3%, n=67), herpes simplex virus (3.2%, n=51), vaccinia virus (7.9%, n=124), poxvirus (5.8%, n=91), and baculovirus (more detailed information is available at www.wiley.co.uk/genmed/clinical). The first step to construct a viral vector for transferring the gene of interest involves the identification of the viral sequences that are necessary for replication and pathogenesis. Then some of the genes are removed to make room for the transgene and to render the viral vector replication-incompetent. Consequently, the vector is unable to replicate within the host, and therefore is safe for delivering genes to human cells or tissues (Figure 1).

There are advantages and disadvantages to all of the currently available vectors; the suitability of the vector, therefore, actually depends on the disease or condition that is being treated. For instance, if the goal of the gene therapy is to increase bone marrow engraftment with the transient expression of a growth factor, the use of chemical transfection or naked DNA transfer methods would suffice. However, if the objective is to provide long-term treatment for an inherited disease, then the use of an integrating viral vector is more desirable. Thus, a vector that might be ideal for treating one defect may not be ideal for another. Driven by the desire to develop the “perfect” vector, scientists are continually striving for novel forms of gene delivery that might become the “magic bullet.” Somia and Verma [3] have proposed that the ideal gene therapy vector should include all of the following properties: 1) easy production at a high titer on a commercial scale with a reasonable shelf-life for transport and distribution 2) sustained or regulated expression of the transgene product that is adjustable to the nature of the disease, 3) absence of immune response against the vector and the transgene product, 4) ability to target specific tissues and/or cell types while avoiding professional antigen-presenting cells, 5) absence of size limitations for the genetic material to be delivered by the vector, 6) site-specific integration of the transgene into the chromosome of the target cell to avoid insertional mutagenesis, or faithful division and segregation if it is to reside in the nucleus as an episome independent of local chromatin environments, and 7) an ability to infect dividing and post-mitotic cells. Unfortunately, none of the currently available gene delivery vectors carry all of these features; however, many vectors have enough of the attributes to make them promising for clinical use.

Candidate diseases

During the last 4 decades, gene therapy for many diseases has progressed from preclinical to clinical studies; these range from monogenic recessive disorders such as hemophilia and cystic fibrosis to more complex diseases such as cancer, cardiovascular disorders, human immunodeficiency virus (HIV), neurological and ocular pathologies. The prevalence of diseases that fall under the scope of gene therapy is enormous and most of them have catastrophic or fatal outcomes. Therefore, gene therapy approach for almost any of the diseases mentioned above has an obvious appeal and rationale. To date, more than 1,540 gene therapy clinical trials have been initiated, and these are continuing or have been completed in 28 countries, using more than 100 genes, including antigens, cytokines, tumor suppressors, growth factors, and deficiency genes [4].

Candidate monogenic disorders that are considered to be good candidates for treatment by gene therapy include the hemoglobinopathies, X-linked genetic disorders, amino acid metabolism disorders, and lysosomal and other storage diseases. Currently, there are more than 4000 monogenic diseases registered in the OMIM database. The ultimate aim in treating monogenic diseases with gene therapy is the correction of the disorder by the stable transfer of the functioning gene into dividing cells (stem/progenitor cells), which will ensure the permanence of the correction [5]. The first recognized successful clinical gene therapy trial involved the treatment of 11 children who suffered from SCID-X1 (Severe Combined Immunodeficiency), an X-linked inherited monogenic disorder caused due to a mutation in the common cytokine receptor gamma chain (γc). In these patients, immunity was not fully developed due to the blocking of T-cell and natural killer cell development as a result of mutation. Unfortunately, the trial in SCID-X1 also exemplified one of the potentially serious side effects of gene therapy. Three of the children developed uncontrolled clonal T-cell proliferation, that is, leukemia, almost 3 years after treatment. This case was associated with the integration of the retroviral vector close to the promoter of the LMO-2 proto-oncogene. As a result, LMO-2 protein expression was up-regulated in an abnormal way and resulted in leukemia [7]. Another candidate monogenic disorder for gene therapy is cystic fibrosis (CF), in which abnormally thick mucus is produced in the lungs of the patients, causing difficulty in breathing and increasing the frequency of serious lung infections. CF is known as the most common inherited genetic disease in Europe and USA, especially within the Ashkenazi Jewish population. The average life expectancy of patients with CF is less than 40 years; hence the treatment of this disease has become one of the prime targets of gene therapy research.

In addition to its use in the treatment of monogenic diseases, gene therapy is also becoming a therapeutic alternative for the treatment of various forms of cancer. Indeed, almost 65% of ongoing clinical trials are related to cancer (more detailed information is available at www.wiley.co.uk/genmed/clinical), an area in which much more promise can be seen; this is also a reflection of the urgent need for new therapies to tackle the escalating incidence of this disease. Several different principles are used to treat cancer, including gene therapy that is targeted at tumor suppressor genes, such as p53, or central signaling molecules, as well as “suicide gene” therapy, in which the transgene is capable of converting pro-drugs (selectively less active drugs) into drugs that are toxic for tumor cells. Furthermore, various gene therapy protocols have been developed to strengthen the host’s anti-tumor immune responses by immunotherapy. Most of these studies have been early clinical trials designed primarily as studies of the safety, applicability, and toxicity of gene therapy. Several of these phase I and II studies have, however, shown partial remission of tumors and, in rare cases, complete remission. However, complete cure of the tumor has not yet been achieved. In some trials, including TP53 gene therapy trials, regression in tumor size has been observed in up to 50% of patients. China has become the first country to license gene therapy as a regular treatment for neck and head cancer; here Gendicine, a replication-defective Ad5 vector expressing p53 from a Rous sarcoma virus (RSV) promoter, is used for therapy [6].

In addition to its applications for cancer and monogenic diseases, gene therapy has become one of the favorite methods in cardiovascular research field. This is in step with the rise in clinical trials for cardiovascular gene therapy from 8.3% to 9.1% during the last few years, becoming the second most popular application for gene therapy. In accordance with the variety and occurrence of cardiovascular diseases, different gene therapy strategies have been developed to tackle each disease on its own terms. The expectation is that gene therapy will provide a new avenue for therapeutic applications in the growth of blood vessels, as well as the protection, regeneration, and repair of heart tissue, the prevention of the reoccurrence of constricted or narrowed arteries following cardiovascular intervention, the prevention of the rejection of a bypass, and risk-factor management [4]. Long-term therapeutic gene expression is required in some diseases, such as hypertension research, where reversal and prevention are the key targets. On the other hand, for some other types of cardiovascular diseases, such as ischemia, atherosclerosis, and restenosis, shorter-term gene control will be sufficient to prevent further progress of the symptoms. Therefore, different gene-therapy vectors have to be considered for the treatment of each specific cardiovascular disorder.

Consequently, gene therapy offers new avenues of treatment for diseases including monogenic disorders, cancer, cardiovascular diseases, infectious pathologies and many more. As we follow the tradition, “God did not send down any illness for which He did not also send a cure (Bukhari)”, gene therapy using either viral, non-viral, or any other novel methods may pave the way for the cure of many diseases that are highly prevalent in the world and which for decades have been perceived as untreatable.

Dr. Ferhat Ozturk is a postdoctoral research associate at University of Nebraska Medical Center.

References

1. Wells DJ. “Gene therapy progress and prospects: electroporation and other physical methods.” Gene Ther. 2004 Sep;11(18):1363-9.
2. Kootstra, N.A. and I.M. Verma, “Gene therapy with viral vectors.” Annu Rev Pharmacol Toxicol, 2003. 43: p. 413-39.
3. Somia, N. and I.M. Verma, “Gene therapy: trials and tribulations.” Nat Rev Genet, 2000. 1(2): p. 91-9.
4. Edelstein, M.L., M.R. Abedi, and J. Wixon, “Gene therapy clinical trials worldwide to 2007–an update. J Gene Med, 2007. 9(10): p. 833-42.
5. http://www.biomedisch.nl/en/gene_therapy_targeted_diseases.php
6. Peng, Z., “Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers.” Hum Gene Ther, 2005. 16(9): p. 1016-27.
7. Cavazzana-Calvo M, Fischer A, Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. 2007 June. 117(6):1456-65

Decisions within the cell: mathematical and algorithmic character

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

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

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

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

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

The genetic engineering procedures in cells

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

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

The R&D department of the genome

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

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

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

Hamza Aydin holds a PhD in biology.

References

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

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

The Structure of DNA

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

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

Genes and the Human Genome Project

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

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

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

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

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

Genomics vs. proteomics

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

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

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

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

Conclusion

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

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

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

Notes

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

The complex nature of genetics and its wide implications for all living organisms from viruses to humans provide raw materials for creative imaginations. In the present scenario, many consider it vital to comprehend all the genetic information necessary to support life on this universe. One of the common constraints on the understanding of genetics is the assumption that genes are the sole causes of all activities of living organisms and can explain all aspects of biological life on earth. For example, some believe the behavior and development of an organism can be predicted, if its genetic information is known-this belief is called “genetic determinism.” However, it is true that neither all aspects of inheritance are in all cases well explained, nor that the mere effect of genes on complex traits is well interpreted. The boundaries of the effects of genes on physical existence, development, survival, and the behavior of organisms are not always simple and straightforward. The capacity of humans for genetic manipulation-at least as it is commonly assumed or claimed-is limited in several ways and some of the basic causes of such barriers have yet to be explained. The focus of this article is to point out the limitations on attempts to appoint genes as the driving force of life.

The Central Dogma

Genes are small fragments of genomic DNA, encoding mRNAs which are later translated into proteins that participate in different biological metabolisms, hence conferring different traits on an organism. The biological functions and transmission patterns of genes over generations were being investigated well before the discovery of DNA as hereditary material and date back to the recognition of Mendel’s laws in the early twentieth century. Genetic information is coded in the form of a short string of DNA called a gene, which is employed in the expression of a trait(s) or mechanism(s) through synthesizing a chain of amino acids called proteins. These proteins either can be stored in different body parts or serve as enzymes in various biochemical reactions such as fighting infections. This flow of genetic information from gene–mRNA–protein synthesis is called the “Central Dogma” in biological sciences. In this biological doctrine, a very solid and predictable mechanism is assumed. Prior to the release of the human genome sequence information, the number of genes in the human genome was estimated as ~100,000. However, this estimate was far more than the actual number of genes (~35,000), which led us to question the validity of the “Central Dogma” as an explanation of the complexity of human beings. Out of these ~35,000, only 300 genes are unique to the human species.¹ This is another blow to the authenticity of the original central dogma theory. Are those 300 genes the foundation of all humankind and do they distinguish us from the rest of the mammals? Reducing humankind to its biology and explaining it based on genes has been questioned extensively and could be the subject of another discussion. But even considering such a view valid for purely practical purposes, the big gap between humans and other mammals cannot be due to the existence of this small number of genes.

Recent scientific discoveries have revealed a key point about the structure of genes-that each gene has a set of sub-segments called exons. Each exon can make a new protein. Hence, the gene can be the template for more than one protein. In the presence of other genes and proteins, the code of a particular gene can yield different kinds of proteins under variable circumstances. The flow of information can be both ways, and hence there are no predetermined factors controlling the flow of information. That means, we might know the information on what genes are present, and we can even decode it to know what is in there, but we cannot be sure what result (proteins in this context) will come out at the end when it is in the context of real life.

From physical characteristics to their genetics

Working back from a particular trait and trying to infer the genes that are involved in expression of such trait is a different approach to reveal the role of genes but surely it is not an easy task. Traits that are expressed by a single gene or a small number of genes are known as Mendelian/qualitative traits and their pattern of inheritance is simple and detection of the gene(s) is straightforward. Some of the disease resistance in plants and blood groups in humans are classic examples of Mendelian traits. The main distinction between such traits and the quantitative ones is their discreteness. For example a human being can have only one of four blood types: A, B, AB or O, and each of these groups is solid and no other blood types exist in between. In this type of trait, the role of a particular gene(s) is usually predictable and the pattern of transmissions over generations both for the future and the past can be inferred.

However, only a small percentage of traits is qualitative and expresses Mendelian inheritance. Most traits, such as intelligence, skin color in humans, height of an organism, seed yield of a grain, and diseases that have genetic causes like cancer, are quantitative traits and complex in nature. The ultimate phenotype (what we can see or measure from a trait) emerges from the joint effect of many genes as well as interaction with the particular environment in which the individual develops. The number of genes that is involved in the expression of a particular trait can be hundreds or even more. An objective assessment of each trait and quantification (called the phenotype) is impractical in most cases and could lead to another discussion. But assuming that we can measure a trait feasibly, the inference of genetic bases could still be controversial. Considerable efforts have been devoted to unveiling the effect of genes in the expression of complex traits whose inheritance pattern deviates from Mendelian inheritance. A special genetic technique, known as genetic mapping, is used to identify multiple genes that underlie a complex trait and this has practical applications for crop improvement. In humans, efforts are directed toward the detection of genes which predispose to complex inherited diseases. In this type of situation, the effects of genes on a trait are additive and can only explain a certain amount of change in the trait that we are interested in. Detection of all genes involved in the expression of a quantitative trait is practically impossible. The environment is an important factor with a pivotal role in the expression of such traits. The term “environment” is not restricted to what is present within the cell or surrounding the cell or individual. It rather refers to larger scale effects in the process of biological life that cannot be explained by genetics and the term can be used interchangeably with non-genetic effects.

One of the most striking examples of the role of genes on the expression of the phenotype is the presence of differences between identical twins. Despite the fact that they have completely identical sets of genes, studies have shown that twins can indicate different degrees of psychiatric diseases such as bipolar disorder.² Similar phenomena may be observed in crop species. In crop breeding programs different varieties are usually tested in different environments. In most cases varieties rank differently based on their performance in different environments.³

Genetic background

Genes that do not code any information for the trait of interest can also be a part of the process of expression of the trait. In other words, certain genes can be employed to stop or alter the function of a particular gene. Modifying the utility of a gene can also be done by a series of complicated reactions within each organism through mechanisms known as epigenetics. This type of alteration in gene function is also observed empirically during the process of transferring genes between different organisms through genetic engineering.⁴ Most transferred genes are silenced (turned off) by different mechanisms in a new organism regardless of patterns of inheritance. This is particularly interesting because it clearly indicates that the existence of a particular gene in the body does not necessarily guarantee that it will be functional. Even if it is functional in one individual, it might be silent in others. Even if a gene is functioning in all the individuals carrying it, the degree of expression may be variable.

The end of genetic determinism

With the discovery of the code of genes, we now know more about the biology of living organisms than ever before, as new genetic tools have enabled us to better understand what kind of information is stored in each gene.

Most of the traits of living organisms are affected by the existence of many genes as well as non-genetic effects (denoted as environment in genetics). Although Mendelian traits can be predictable to some degree, yet we can not completely infer all the genes that are employed in the expression of a complex trait, nor the amount of contribution from each single gene and portion attributed by non-genetic factors. So we cannot determine the presence of genes by simply observing the phenotype or expression of a trait.

Considering each individual gene separately will allow us to understand its possible functions more clearly and accurately. Nevertheless, the knowledge of possible functions and structure is not enough to predetermine if the information coded in the gene will be used by the organism, and, even if it will be used, how much of that information will be processed is uncertain. Whether the information that is processed will be observed or not is another ambiguity.

Assuming that we can and will know all components of life by having the knowledge of genes is known as genetic determinism. In some cases, genes are described as independent entities that drive living organisms and manage life because of the assumption that their presence will be enough to predetermine all the biology and the behavior of an organism.

Simply, in order for a gene to be an independent agent by itself, it needs to have the knowledge of all other genes as well as all the non-genetic factors for expression of a simple trait. In reality, genes contain a very limited amount of knowledge which makes them no more than tools or parts of living organisms that are employed in the existence of life on earth. Biological life itself is incredibly complex and its sustainability requires a more comprehensive knowledge that is beyond our current understanding based on the genetic code.

Seyyidhan Mirza is a PhD candidate of Plant Breeding, Genetics, and Genomics. He can be contacted at seyyidmirza@gmail.com.

Notes

1. Siepel A., M. Diekhans, B. Brejová, L. Langton, M. Stevens, C. L.G. Comstock, C. Davis, B. Ewing, S. Oommen, C. Lau, H. Yu, J. Li, B. A. Roe, P. Green, D. S. Gerhard, G. Temple, D. Haussler, and M. R. Brent. 2007. “Targeted discovery of novel human exons by comparative genomics.” Genome Research. Cold Spring Harbor Laboratory Press; ISSN 1088-9051/07; www.genome.org
2. Cardno, A. G., Rijsdijk, F. V., Sham, P. C., Murray, R. M. & McGuffin, P. “A Twin Study of Genetic Relationships Between Psychotic Symptoms.” 2002. Am. J. Psychiatry 159, 539-545
3. Epinat-Le Signor, C., S. Dousse, J. Lorgeou, J.B. Denis, R. Bonhomme, P. Carolo, and A. Charcosset. 2001. “Interpretation of genotype x environment interactions for early maize hybrids over 12 years.” Crop Sci. 41:663–669
4. Kooter, J.M., Matzke, M.A., and Meyer, P. 1999. “Listening to the silent genes: Transgene silencing, gene regulation and pathogen control.” Trends Plant Sci. 4: 340–347