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.

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.

Cancer is a major cause of illness and death in developed countries. The risk of death from cancer has also been increasing in the less developed countries. As improvements in medical care have reduced deaths from infectious diseases and increased life expectancy, cancer has become the leading cause of death in many societies. For example, according to the American Cancer Society, about one in three people in the USA will develop cancer at some point in their life, and about one in four will die from it. Each year about 500,000 individuals die of cancer, a rate of about one death per minute, and more than one million new cases of cancer are diagnosed annually in the US. Currently more than 10 million individuals are receiving medical treatment for cancer in US hospitals and medical centres.

What are the causes of cancer?

Scientific evidence gathered over the last hundred years has dispelled the superstition, once prevalent, that cancer is a contagious disease. But, despite significant advances in the last decade, its underlying mechanisms are still a mystery.

The link between cancer and genetic mutation was shown early in this century: normal cells mutate into malignant ones because of changes in chromosome constitution.

There are four points which support the idea that cancer has a genetic origin:

1. More than 50 forms of cancer are known to be inherited to one degree or another
2. Some tests detecting mutations have shown that most environmental toxic agents which are called carcinogens are also mutagens.
3. Work with cancer-associated viruses has revealed the presence of some mutant genes, known as oncogenes, that promote and maintain tumour growth.
4. The chromosomal abnormalities found in particular forms of cancer, especially leukemia.
5. The environment and behaviour can also play a significant role in the genesis of cancer.

The existence of high rates of specific cancers in particular families has been known since early in the 19th century. Many explanations have been offered for this phenomenon, including multiple gene inheritance, environmental agents or even mere chance.

Hereditary forms of cancer

Recent advances in cancer research have provided some clues about the relationship between mutant genes and the cellular events that lead to tumour formation. Experimental evidence suggests that as few as two mutational events may be sufficient to cause a cell to become cancerous (see Figure I). In those forms of cancer that show a heritable predisposition, the first mutation is present in the germ cells and is transmitted genetically. The second mutations are acquired by somatic cells through spontaneous replication errors or exposure to environmental agents that cause genetic damage, resulting in cancer. On the other hand, not all individuals who inherit the first mutation will develop cancer.

If the second mutational event does not occur, then no tumour will develop. Research has focused particularly on two classes of genes in carcinogenesis: tumour suppressor genes which normally function to suppress cell division, and proto-oncogenes which normally promote cell division. 

Tumour suppressor genes

Tumour suppressors are detected in the form of chromosomal deletions (or other inactivating mutations) that are tumorigenic. The strongest evidence for their nature is provided by certain hereditary cancers. There is also now evidence that changes in these genes may be associated with the progression of a wide range of cancers. About 10 tumour suppressors are known at present. These genes act at certain points to inhibit cell division. These and or their gene products must be absent or inactive for normal cell division to take place. If tumour suppressor genes become deleted or inactivated by mutation, control over cell division is lost, and the cell can proliferate in unchecked fashion. The example of breast cancer illustrates how mutations in tumour suppressor genes are involved in the development of cancer:

The genetic link to breast cancer

In the USA, the ratio of women getting breast cancer is approximately 1 in 8. It is the most common form of cancer in women: 46,000 women die and 182,000 new cases are diagnosed each year. Epidemiological factors may also be involved in breast cancer, but geneticists have focused on the question – Is there a genetic predisposition to breast cancer? Their answer, for the present, is Yes: though involved in only about 5% of all eases, a particular gene has been identified and located on chromosome 17. It is responsible for susceptibility to a form of breast cancer that appears in the third and fourth decades of life. About one in 200 females inherits this gene, and 80% to 90% of these will develop breast cancer. Besides breast cancer, a gene has been found on chromosome 17 in sufferers from astrocitoma (brain tumours), colon, lung and bone cancers. This finding suggests that there is a mutation on this gene (called p53), and as a result the cells start growing abnormally.

The Future

Investigations into the tumour suppressor genes are an example of the recent progress in molecular aspects of cancer research. A better understanding of molecular carcinogenesis and molecular epidemiology will eventually decrease the quantitative and qualitative uncertainties associated with the current state of cancer risk assessment. It may be possible to immunize patients against their tumours by using these findings about genes-cancer relationships. Indeed, determination of the type and number of mutations in p53 and other cancer-related genes in tissues from ‘healthy’ individuals may allow the identification of those at increased cancer risk and their consequent protection by preventive measures.

Although there have been many and most welcome developments in the diagnosis and treatment of diseases, including cancer, there is a definite and reliably cure only for some of the infectious diseases. However, we firmly believe there are definite remedies for all diseases in the universe except death.

References

• HARRIS, ADRIAN L. (1990) ‘Mutant p53-The commonest genetic abnormality in Human Cancer?’ The Journal of Pathology.
• HARRIS, CURTIS C. (1993) ‘p53: At the Cross-roads of Molecular Carcinogenesis and Risk Assessment’, Science, 262.
• CUMMINGS, M. (1994) Human Heredity, West Publishing Company, St Paul. Lewm, B. (1994) Genes 5, Oxford University Press, New York.
• LEWIN, B. (1994) Genes 5, Oxford University Press, New York.

There has been strong opposition to the idea. The issue was discussed in the U.S. and Europe as long ago as the early 20th century. In 1980, the U.S. Supreme Court held in Diamond v. Chakrabarty that: ‘anything under the sun made by man’ is patentable. The court considered a distinction between a product of nature and a product of human invention or intervention as the decisive factor, rather than the distinction between sentient life and insentient matter. In ex Parte Allen, the Board of Appeal held that an oyster was patentable because it had been genetically altered by human intervention. In the end of the U.S. Patent Office ruled non-naturally occurring non-human multicellular living organisms, including animals, to be patentable. More recently, in 1988, Harvard University was granted a patent on a transgenic mammal named ‘Once Mouse’.

Is the situation any different in Europe? In Germany, inventions in the field of biology were not, in principle, excluded from patent protection, the Federal Supreme Court decided in the Red Dove. The European Patent Convention or EPC, signed in Munich and ratified in 1977, came into force on 1 June 1978 in the member states. Article 53 of the EPC provides that European patents shall not be granted in respect of:

a. inventions, the publication or exploitation of which would be contrary to ‘public order’ or morality, provided that the exploitation shall not be deemed to be so contrary merely because it is prohibited by law or regulation in some or all of the contracting states;

b. plant or animal varieties or essentially biological processes for the production of plants or animals. This provision does not apply to microbiological processes or the products thereof.

This article contains three exceptions to patentability of plant and animals.

1. Animal varieties and plant varieties.

2. Essentially biological processes for the production of plant and animals.

3. Inventions which are contrary to ‘public order’ or ‘morality’.

1. What is the meaning of the term variety?

This question was debated by the Examining Division’s decision (EPOR 4 (1990)) in regard to Once Mouse. The application was made by Harvard University for a patent for a genetically modified animal which was to be used to cure cancer.

The application was refused:

a. on the grounds of non-reproducibility under Article 83 of the EPC. Although the application was based on claims related to all non-human mammalian animals, actual tests had only been done on mice: it could not be assumed that the same manipulation could be successfully performed on other mammals without inventive skill; and,

b. on the grounds that the legislators had intended to exclude animals in general from patentability under Article 53 (b).

However the Board of Appeal did not see any reason to limit the claims under Article 83. Also, the Board did not agree with the Examining Division’s interpretation of Art 53 (b) as excluding animals as such from patent protection. They pointed out that the legislators must have intended the phrase ‘animal varieties’ to be more narrowly construed than ‘animals’. The Board, therefore, held the question to the Examining Division.

On reconsideration, the Division decided that ‘Once Mouse’ did not fall under the terms of the ‘variety’ exemption. It concluded that in relation to Article 53 (b) claims directed to non-human mammals generally did not fall within the scope of the terms ‘animal variety’, (race animale).

The ‘variety’ exemption was also considered in the Giba-Geiy Case by the Technical Board of Appeal.

In- this case, the claimed invention satisfied the requirements of patentability but the Examining Division refused to grant a patent because the subject matter fall into scope of the Art. 53 (b).

Contrary to the Division’s view, the Europe Patent Office (EPO) Technical Board argued that 53(b) excludes only plant varieties and it is clear that ‘plant’ is different from ‘plant varieties’. According to the Board, ‘plant variety’ means stability of characteristics within specific tolerances after every individual propagation or propagation cycle. The Board of heed that 53(b) excludes ‘only the plants or their propagating material in the fixed form of the plant variety.’

2. Another problematic clause under Article 53(b) concerns ‘essentially biological processes for the production of plants and animals’ which are excluded with the proviso that ‘this exclusion does not apply to microbiological processes or products thereof’.

Two main question arises here. Firstly: what differentiates ‘essentially biological processes’ from ‘microbiological processes’?

Llewelyn has assumed that ‘an essentially biological process could be defined, most simply, as one where natural methods are the dominant influence’. The EPO defined ‘essentially biological process’ as dependent on the extent to which there is technical intervention by man in the process. If such intervention plays a significant part in determining or controlling the result the process will not be an ‘essentially biological’ one.

It has been held by the EPO Board, in the context of plants in Lubrizal/Hybrid Plants, that the meaning of ‘essentially biological process’ must be judged on the basis of the essence of the invention, taking into account the totality of human intervention and its impact on the result achieved.’ Human intervention may also mean that the process is not ‘a purely biological’ one even though the intervention made by only a trivial contribution.

The Draft Directive established a new and different approach, namely that a distinction must be made between naturally occurring substance itself and the product in a useful form, which results from human intervention in isolating it from its natural environment.

Art 53(b) says that ‘essentially biological processes’ are not patentable but the Draft Directive provides that this only covers traditional biological breeding activities thereby and rescues the interventions in ‘essentially biological process’ from non-patentability.

The most significant element of Article 53(b) is its inclusion of the products of microbiological processes. This means that a plant or animal produced by a ‘microbiological process’ falls outside the scope of the exclusionary provision of Art 53 (b) and is therefore patentable. It could be said that the aim was specifically to enable products of microbiological processes to be patented, i.e. all genetically engineered plant and animal.

Again, the problem is one precise definition. How does one decide that a process which has been carried out is a ‘microbiological’ one? EPO guidelines explain that ‘microbiological’ covers the processes used by micro-organisms and processes used for producing micro-organisms. Also, ‘micro-organism’ includes material such as plasmids and viruses (which have been used to create new plant genetic matter) and cell lines. All such process are patentable. The Draft Directive similarly rules (in its Article 5) that processes which either use or operate upon a micro-organism, or result in a micro-organism, should be considered microbiological and thus eligible for patent. It goes further: ‘the word micro-organism shall be interpreted in its broadest sense as including all microbiological entities capable of replication, e.g. as comprising, inter alia, bacterium fungi . . . and cells.’

3. The third exception is on the grounds of immorality. Art 53 (a) provides that a patent should not be granted in respect of inventions, the publication or exploitation of which would be contrary to ‘Public Order’ or ‘morality’. In other words, if the public considers an invention ‘immoral’ a patent would not be granted.

But, the Examining Division ruled in regard to ‘Once Mouse’ that irrespective of whether the public considered it moral or immoral, such inventions incontrovertibly assisted mankind in the care of ‘widespread and dangerous’ diseases. The Technical Board of Appeal pointed out in its recommendations to the Division that the possible suffering to animals and risks to the environment should be balanced against the invention’s usefulness in meeting human needs (diagnosis, treatment, food supply for a rapidly growing world population) on the other hand. The Division stated that ‘the invention would reduce the overall level of animal suffering by reducing the number of animals used in conventional animal testing.

Considerable doubts remain. Whether or not ‘Once Mouse’ may help save people dying from cancer, who is to guarantee that mice or other animals will not be manipulated to which achieve a cure for baldness or other trivial (but commercially ‘compelling’) purpose. What is the excuse for creating a very unhappy, transgenic rat to cure a widespread but non-lethal condition such as acne?

Genetic engineering should be the subject of general legislation rather than ‘patent law’ especially in respect of ‘immorality’. 

Conclusion

The development of new features in plants and animals using microbiological methods is a long, difficult, expensive process with no guarantee for success. Therefore patents which have been granted by appropriate and competent bodies need to cover not only the first generation of the altered animals or plants but also their progeny which are then the result of natural breeding: and this was allowed in the claims of the Harvard Patent.

Despite strong arguments on several grounds, a new invention related to living matter should not be prevented from securing a patent. It is also our view that the distinction between patentable and non-patentable should be made on the basis of human intervention (especially in relation to microbiological processes) rather than on the basis of sentient or insentient matter.

However the patentability of human life or any part of human life must always be regarded as unacceptable in principle because human life should not be subject to commercialism: it would open the way to a new form of slavery.

• References
• CHRISRIE, A. (1989) ‘Patent for plant innovation’ EIPR, 3.
• CORREA, C. (1992) ‘Biological resources and intellectual property rights’ EIPR, 5.
• NOTT, R. (1992) ‘Patent protection for plant and animals’ EIPR, 3, p.79.
• PAVER, M. (1992) ‘All animals are patentable but some are more patentable than others’, Patent World, March, 9.
• WHAITE, R.& JONES, N. (1989) ‘Biotechnological patent in Europe’, The Draft Directive, EIPR, 5.