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

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

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

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

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

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

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

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

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

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

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

The time machine

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

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

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

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

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

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

Note

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

References

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

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

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

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

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

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

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

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

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

Notes

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

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

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

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

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

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

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

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

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