A lottery ticket and a packet of cigarettes, please

This essay was written by Martin Webb and was first published in the 2005 Mill Hill Essays.

Buying either item in this title is a gamble. In one case, there is a chance of riches, in the other a chance of cancer. We do not need to know the mechanism by which winning numbers are chosen in the lottery in order to win, but we should understand and realise the odds. With cancer, we want to change the odds as well as understand them. Every individual can control how much they spend on each form of gambling, and hence their own chances of winning the lottery or losing out to cancer. There are many types of cancer where the individual cannot control their chances so easily and scientific research has a large role to play. There is a vast amount of research on cancer, seeking both to understand its causes and to improve treatment. Many advances have been made, and continue to be made, to fight cancer itself and its effects. In spite of this, cancer remains a prominent disease and affects many. Each case of cancer affects an individual and their family greatly. Sometimes there is tragedy, but these days very often hope and joy coming with remission. Whatever the outcome, the result may be life changing, for we often consider cancer as a brush with death. The reason for the continuing high incidence of cancer lies to some extent in the fact that many other diseases are no longer commonplace in western societies. A number of factors, including public health improvements and widespread containment of infectious diseases, mean that each generation is living significantly longer than the previous one. There is therefore a longer period of time for the factors that lead to cancer to affect us. By the time we are 65 years old, about one in ten of us will have been diagnosed with cancer. After 65, a further two of the ten will be diagnosed. Cancer is a disease mainly of the latter part of our lives, although it can affect human beings of any age.

Most people can understand the idea of infectious agents, such as bacteria, causing a disease, but often the agents that cause cancer seem much less obvious. Various chemicals, for example those present in cigarette smoke, are known to be causes of cancer, as is ultraviolet light from the sun. A susceptibility to cancer can also be inherited. Cancer often takes the form of a tumour or an area of tissue where growth is abnormal. There are different lengths of time over which a cancer may get worse, or regress. Sometimes the cancer affects a vital part of the body, such as the lungs, but it is often the spread of a cancer beyond the original site (metastasis) that is a major factor in it becoming fatal. However, the events that lead from these physical causes to the clinical effects are complex. Apart from the various causative agents, the laws of chance interact with those of chemistry and biology to determine if the series of events will occur that will lead to cancerous growth.

The processes which give rise to cancer occur mainly within our cells, disrupting the complex balance that is required to keep each cell working properly. Normally new cells form, operate their required function and then die. A wide variety of mechanisms are present within our cells to ensure that this cycle of cell life and death works properly. Failsafe mechanisms provide back up should there be problems. Mechanisms to kill the cell can also be instigated should it start operating incorrectly. Within higher organisms, such as man, there are many different types of cell that must develop and fulfil their proper role. Not only must they all function correctly, they must do so at the right times in our life and at the correct places in our body. A complex array of signals to control all this is laid out in our genetic blueprint. The chromosomes we inherit from our parents contain this blueprint in molecules of DNA and this is present in almost every functioning cell.

Every day of our life new cells are generated as our bodies need them, for growth or to replace old, dying or malfunctioning cells. In higher organisms most specialised cells do not themselves give rise to new cells but special classes of cells called stem cells perform this function. Each new cell forms from a pre-existing cell and as this occurs, the genetic blueprint is copied so that each new cell has an exact copy. In amongst the many instructions carried in our genes are those on how to perform this copying and deliver a copy to each new cell.

Errors (mutations) can creep into this blueprint in a cell and one outcome of such errors may be cancer. Mutations can occur spontaneously, through a chemical agent or radiation for example. The errors produced by these processes will then be replicated in any new cells formed from such an altered cell. Errors can also occur during the replication of the DNA: in that case, the copy made for the new cell is not quite exact. If such errors are in the egg or sperm, which each contain only one copy of half the complete DNA of a fertilised embryo, they will be passed on to all the cells of offspring formed from them. It has been estimated that there is roughly one chance in ten of a new mutation appearing in the genes of an offspring in this way, though the vast majority of mutations are likely to be harmless. Cancer is not the only outcome of mutation. In fact, given how often errors occur, it is a very rare outcome. Most mutations have no effect on the functioning of cells. Indeed such changes in the gametes give mankind its genetic diversity: my DNA differs slightly from yours. Mutations also are fundamental to evolution. As DNA gradually changes through successive generations, slight changes in the functioning or efficiency of particular processes will occur. If it is a change for the better, individuals who carry that mutation will have an advantage, for example in adapting to a changing environment. Such mutations would gradually spread among the population over many generations. In contrast, mutations that gave rise to poor functioning would give those individuals a disadvantage over evolutionary time. However, another possible outcome of mutations in the DNA is more extreme. A particular function might be completely destroyed so that the cell becomes unviable. The cell dies and usually there are no further consequences as new cells without the lethal mutations can then replace the dead cells.

So mutations that lead to cancer represent a very small fraction of all changes. Here the new cells are viable but they have altered function: they are to some extent “out of control”. This can occur in a number of ways. For example, some genes determine the control of formation of new cells. The control processes are balanced by being switched on and off through a series of steps. A mutation in one of these genes might lead to one step being permanently switched on and hence to cell division with a lack of control. This can result in cancerous growth of these cells. The DNA in our cells is composed of molecules, and its replication, repair and even mutation are all chemical processes. Many properties of the DNA are based on chemistry of these molecules. Within each cell there is a myriad of chemical reactions occurring and the predominant chemistry is of one element, carbon. This has an immense diversity of reactions in which it can participate and types of chemical structures that it can form. These range from very stable structures, which for the cell means long–lived, to the transient, when speed and change are essential. The DNA molecule is formed using the chemistry of carbon, but also contains another mainstay of cellular chemistry, phosphate. DNA consists of a series of similar molecules, called nucleosides, stably linked together by phosphates into a long chain. Each nucleoside consists of a sugar and one of four different types of base that provide the genetic code. Each gene has a specific sequence of bases that the cell translates into a specific protein. The function of each protein is largely determined by its sequence. Each gene also includes instructions of where to start and stop the translation and there are also specific sequences of bases that participate in instructions of switching on translation. Every cell has thousands of different proteins that control and operate all its functions including growth, moving molecules around, and generating energy to perform other functions.

It is the physical and chemical properties of the repeated nucleoside-phosphate units that lead to the double helix structure: each base on one DNA strand interacts specifically with its partner base on the other strand. Each of the two strands contains the same information. The diversity of carbon chemistry is its strength and utility, but it also opens up the nucleosides to the possibility of a variety of unwanted chemical alterations. This can lead to DNA damage induced by other chemical reagents (carcinogens) or by radiation. Thus carcinogens are chemicals that can enter the cell and directly or indirectly cause chemical modification of the DNA. This might be through breaking links in the chain of units that make up DNA. Often, it is one or more bases of the DNA that are damaged by such agents. Once such chemical damage has occurred the sequence of bases cannot be successfully translated into the exactly correct protein. The damage may lead to misreading of the base, so a mutant protein results. Radiation can be natural, such as ultraviolet light from the sun, or radioactivity from natural or manmade sources. In either case it may have sufficient energy to cause alterations in bases of DNA.

Errors creep into our DNA quite frequently, and organisms, from bacteria through to man, have developed complex mechanisms to correct them. When DNA is replicated in cell division, it is checked at each step to ensure that the new copy is the same as the original. Given that there are a billion such steps each time a cell divides, this checking is very precise. The vast majority of errors are detected and corrected. Cells use a variety of strategies to prevent or deal with damage to DNA. Enzymes within the body can intercept and destroy certain cancer–causing agents before they can cause mutations. Enzymes are proteins that carry out specialised tasks within the body, by enabling specific chemical reactions to occur, in this particular case the breakdown of carcinogens into harmless molecules. If damage does occur, it may be that other, undamaged genes can replace the function of one that is damaged. DNA repair mechanisms can deal with much of the damage that occurs. If one of the four different bases is damaged a wide array of repair enzymes come into play. Repair enzymes can reverse specific forms of damage to DNA and return the base to its correct structure. Other forms of damage are dealt with by cutting out the damaged nucleoside, or even a section of DNA, and replacing them with the correct version. This array of repair mechanisms can normally cope with typical rates of damage. In spite of all the repair mechanisms though, errors can get through and cells will sometimes contain damaged DNA.

The repair enzymes are themselves proteins and hence are produced using particular genes. It is possible that mutations in these genes can result in the loss of the repair mechanism. Any individuals carrying such mutations will be less able to cope with DNA damage and will suffer an increased risk of permanent damage to one of the genes in their cells that can lead to cancer. If mutations in DNA repair enzymes are passed on to the next generation then we can see how some types of susceptibility to cancer can be inherited.

Once errors to DNA have escaped this array of prevention and repair mechanisms, then some mutations can lead to cancer. Two ways are outlined next. Many proteins are involved in controlling cell division and a number of key proteins are known to be susceptible to cancer–causing mutations. One example is a protein called Ras. Ras has been described as a molecular switch. It can take two forms: in one the switch is on, in the other it is off. In normal cells Ras is switched on as part of the complex machinery to control cell growth and division, but it can be switched off when appropriate. While many mutations to Ras will not cause cancer, several will do so. These mutations in Ras have frequently been associated with several different cancers and this mutated Ras is called an oncogene. Harmful mutations produce Ras that is always switched on and so control is lost. This may lead to the uncontrolled growth of cancer. Another type of gene where mutations may lead to cancer is a tumour suppressor gene. Such genes normally function to prevent cells from growing and dividing out of control. This might be, for example, when previous mutations have already damaged the control of cell growth. If a tumour suppressor gene is damaged, however, it can no longer provide this restraint. Thus an accumulation of several mutations are required to overcome the natural control process.

We can now look at how understanding the changes in the cell might help to clarify certain aspects of prevention, detection and treatment. The body might be able to cope with low levels of cancer-causing agents, but not when these levels become too high. In practice the details remain unclear. Is there a “safe” level of each agent, a threshold below which a chemical or radiation is harmless? Certainly regulatory bodies give maximum safe levels, for example for some types of ionising radiation. In part such levels are a practical measure, as it is impossible to eliminate completely many agents. Depending on where we live we can experience low background radiation from natural radioactivity in some types of rock formations. In part, designation of maximum safe levels reflects the amount of a particular agent that would cause significant risk within a lifetime. Detailed understanding of how particular agents damage DNA and how repair mechanisms cope may lead us to be more precise on danger levels. Indeed different individuals may cope with agents to different extents, depending on their genetic inheritance or their lifestyle. We all know that smoking is a risk. The extent of that risk is almost entirely under our own control. Lung cancer is the major type of cancer in men in the West. Stop smoking and the risk of lung cancer will diminish to almost nothing. There remain arguments of the risks of secondary smoke, although it seems likely that it is the cause of a small but significant number of deaths. Similarly, ultraviolet light from strong sunlight can cause skin cancer, and we know the importance of sunscreens on the beach. But during the year many of us accumulate more time in the sun while going to and from work or the shops. Should we put sunscreen on each time we go out? Of course, we balance risk with practical considerations.

As more genes are identified that may carry a susceptibility to cancer, it becomes easier to identify individuals carrying mutated genes, through tests on their DNA. Screening programmes for the early onset of cancer can be targeted at such susceptible individuals and their families. We can also target screening by age, given the age profiles for which certain cancers are most common. Since particular gene mutations have been identified that are early steps in cancer onset, intervention to correct the mutations could prevent cancer from subsequently occurring in that individual. This type of treatment, to overcome a particular mutation, is called gene therapy and provides hope for the future. Several methods have been suggested, including replacing the damaged gene with a healthy one. It may also be possible to stop the damaged gene producing damaged protein so that only the undamaged genes would produce protein. A number of these approaches are being developed and tested. While cancers have a common origin in gene damage, the fact that different genes may be affected in different cancers means that such treatments are likely to require many targets, each one associated with particular cancer types.

Cancer treatment is often more effective if performed at an early stage of the disease. The area of damage is small and it is unlikely to have spread to remote parts of the body. Treatment can use the fact that cancerous cells undergo relatively rapid growth. Chemotherapy in part targets rapidly dividing cells. The fact that mutant proteins have different properties from the normal protein also means that potentially it is possible to design a molecule that will intercept the mutant protein alone. Detailed understanding of both structure and function of such proteins will provide useful guidance to developing this approach. The field of cancer treatment is rapidly changing. Scientific research has led to better understanding of basic processes within the body that are disrupted in cancer. While this basic understanding in itself provides no immediate cure, it is allowing treatments to advance and to be tailored more precisely to particular cancers. It is also leading to better understanding of risks, and hence to prevention.

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