A pizza has become a household answer to fast food. A 30 minute delivery boosts its sale and the diner’s appetite has the perfect amount of time to build up till the delivery van pulls up to his door. This cheesy delight is served best with a dollop of tomato ketchup on the side. Juicy red tomatoes and spices which come packed especially for you to delight in that tangy-sweet mixture. Tomatoes have become a staple world over. There is not a cuisine that doesn’t employ tomatoes as taste and colour donators. Their uniqueness lies in their DNA. DNA or deoxyribonucleic acid is what contains genes or units of heredity that are passed down from one generation to another, ensuring that each tomato is as flavoursome as its parent. The industrialisation of our planet and subsequent loss of a clean environment has caused a lot of DNA changing material to be released in the atmosphere. These are called mutagens. They can be radiation, carcinogenic compounds or even excess of a carbon based gas. They cause the structure of DNA to change rendering our tomato to probably be different than the parent… different in not a good way. Many studies have been conducted to define how mutagens affect the DNA. How these genes change their expression and how can this affect all of us.
Let’s move a little back and look at the scene when there is no mutation. Mutation changes the expression of genes. Expression of genes is continuously being altered and defined even in a normal cell, but perhaps in a healthier way than in a mutated cell. This mechanism of controlling gene expression naturally is what defines the study of EPIGENETICS.
The word ‘epigenetics’ has been derived from a combination of the Greek word ‘epi’ and genetics. Epi means over, above or outer and genetics is the study of genes. Together, the word means the study of those aspects which surround and affect genes. Therefore, epigenetics is the study of functionally relevant modifications to the genome that do not change, modify or mutate the nucleotide sequence. It relates to the age old discussion of Nature vs. Nurture and asserts to Lamarckism, both of which will be discussed further in this article.
To understand what epigenetics actually is, we need to know what an epigenome is. Epigenome is to epigenetics what genome is to genetics and hence forms the basis of the study. Epigenome is the switch or collection of switches that tell a gene when to turn on or off. These switches are proteins or other molecules and do not constitute of nucleotides in any way. They are responsible for inheritance of changes caused by the environment in the individual. Such changes are not translated into the DNA and therefore, it is not and does not determine evolution. Epigenome is a basic response to environmental stress. If a particular nutrient is abundant in the medium in which a microbe is being cultured, the microbe’s genetic mechanism of producing that same nutrient will be switched off as there is no need for it to be produced by it. This is regulation of a metabolic pathway and the switching on and off of genes is somewhat similar but not exactly like this. An epigenome can be inherited by the progeny but the change will fade after a few generations. These generations could number from two to hundreds. These changes determine whether you talk loudly or whisper. They also determine major things like memory, obesity and immunity. Thus, an epigenome adjusts genes. It does not add or delete them.
Nature vs. Nurture and Lamarckism
Nature vs. Nurture and Lamarckism basically point us into the same direction. They both say that it isn’t only the genetic code that determines our states but also our lifestyle and environmental factors. While Nature vs. Nurture points towards a healthy and hygienic lifestyle, Lamarckism disagrees with some aspects of Darwinism. Survival of the fittest was Darwin’s theory and it has been proven to be true time and again. But, Lamarck suggested that it isn’t only the DNA or the genome that makes us strong. It isn’t only via the evolution of a species into a better one or by inheritance of adaptability owing to better characteristics via the genome that one species survives and the other doesn’t. It is possible for a species to survive a rough environmental phase by simply altering their epigenome. Such changes may or may not be inheritable and if they are inherited, will last only for a few generations or till the stress factor is removed and the surroundings are hospitable again.
What causes epigenetic changes?
This discussion brings forth the question of how epigenomic changes work. How exactly do they occur? What is the mechanism and what influences this change of state? The answer is simply a change in the environment. A change that causes the activity of one gene to switch on or off. This causes the release or no release of the associated enzyme or protein via DNA translation and RNA (ribonucleic acid) transcription. These proteins in turn affect the action of other genes for which they are promoters or inhibitors. Thus, a cascade of changes is generated which affects the organism’s entire metabolism and hence, the organism’s body.
The carriers of change are:
- DNA Methylation
- Chromatin Remodelling
- RNA transcription and associated proteins
- Structural inheritance Systems
DNA methylation is the phenomenon where a purine or pyrimidine base pair (mostly adenine and cytosine) are methylated at certain sites by the simple addition of a methyl (-CH3) group to their respective nitrogen and carbon atoms. Methylation occurs at the fifth position of the cytosine pyramid and at the sixth nitrogen position in the purine ring of adenine base.
Most unwanted and extra methylations are removed at the embryonic stage. The expressed and wanted methylations suppress the expression of viral and deleterious elements. They assist in development of cancers and are major players in formation of the chromatin structure. Too many methylation or too little methylations will cause the chromatin formed to be different than normal, thereby causing chromatin remodelling. In adults, methylation of the CpG areas is common.
These are areas where cytosine and guanine base pairs occur consecutively on one strand. This methylation is not found in embryos. Long term memory storage has been found to be regulated by DNA methylation. Methylated DNA has a tendency to be bound to Methylated DNA binding proteins or MDBs. These lead the non-transcription of the bound DNA regions. Thus, this phenomenon may physically impede the expression of genes.
As discussed earlier in this article, transcribed RNA may code for proteins that are essential in maintaining gene activity. A single malfunction or change leads to a cascade of changes which may lead to the changing of the very basis of the organism’s functioning. The proteins Hnf4 and MyoD control the expression of liver and muscle genes. Epigenetic changes here may be caused by generic chromatin modifying complexes, double stranded RNA or via diffusion of certain transcripted proteins from one cell to another via gap junctions or in syncytia (condition of a cell which has multiple nuclei).
Mostly, these changes are caused by RNAi or RNA interference which is the phenomenon where rogue RNA strands interfere with the organism’s genetic expression without mutating the nucleotide sequence.
A prion is an infectious form of protein that does not fold into a discrete protein unit. They have a lethal property of changing the normal proteins (similar to the one’s they were supposed to fold into but did not) into prions like themselves, thereby causing phenotypic changes in the organism without ever affecting or altering the genome. These changes may or may not be inheritable. Some fungal prions produce heritable changes and are therefore termed as epigenetic changers. PSI+ cells in yeast have prions that make ribosomes read through the stop codons and translate a lot of non-sense protein. This delays the translation of useful protein and also translates a number of prion precursors and waste protein which may or may not be harmful to the organism.
Studies and Experiments
Many experiments have been conducted to prove the theory of epigenetics. The most successful and pioneering one was performed by Dr. Lars Olov Bygren. He belongs to the small farming village of Norrbotten in Sweden. This village is heavily dependent on environmental conditions to have a good or bad harvest. A bad harvest means a famine year while a good harvest will mean plentiful for everyone. Dr. Bygren studied individuals who were born in 1905 and two of their subsequent generations. The subjects of the first study were all males. It was shown that parents who had undergone many cycles of famine and then plentiful of food and then famine again had children with higher BMI (body mass index) than the parents who had sufficient food to eat all their lives. Bygren suggests that the obesity gene (FTO) was greatly expressed in the population’s progeny. Another study was conducted on pregnant women who had undergone the same famine and splurge sequence. Their children were at a higher risk of obesity.
Avon Longitudinal Study of Parents and Children (ALSPC) further studied the effects of certain environmental factors on pregnant women and subsequently, the babies they delivered. It was found that the usage of peanut baby oil caused the infants to be allergic to peanuts. The expecting mothers who had high anxiety levels gave birth to asthmatic babies. Children who were kept in highly sterilized and hygienic condition were more prone to eczema than others.
Bygren and his team also conducted studies on fathers who had started to smoke around the age of eleven. Their children too displayed a higher BMI than their peers.
Animal experiments have also proven the theory of epigenetics. Fruit flies were exposed to a drug called geldnamycin for one generation. This drug caused unusual outgrowths to occur on the fly’s eyes. This effect was inherited up to thirteen subsequent generations even though the flies were not exposed to the drug after the first generation.
Jirtle and Waterland conducted epigenetic experiments on mice. They worked with two sets of mice, each with pronounced Agouti gene. This gene’s expression causes the mouse to have a yellow coat and be highly prone to diabetes and obesity. It was found that just by providing a diet high in vitamin B 12 content, one of the sets of mice produced healthy brown pups with no high risk of obesity or diabetes.
Studies on mice have also shown that the mice whose parents were given special exercises on building memory or intelligence were innately more intelligent than other mice whose parents were not conditioned.
Epigenetics has led to a whole new phase of medical advances. Scientists are developing drugs which can counter cancer epigenetically. Research is also continuing on combating Down syndrome, Autism and Alzheimer’s Diseases via epigenetic treatments. Cancer treatment research has taken the forefront due to the widespread nature of the disease. The first epigenetic drug to be approved was Azacitidine in 2004. It attempts to cure blood tumors, mostly MDSs (Myelodysplastic Syndrome). It has shown to increase life expectancy of the patient by nine months.
Apicidine, Procaine and Zebularine are also epigenetic cancer drugs which are currently in preclinical research stages.
Epigenetics seems to be the answer to many unknown questions. Whether its knowledge will help mankind save themselves from various diseases or whether it will enable us to understand inheritance better is unknown. What is known though, is that our lifestyle determines the future of our progeny. The future is literally in our hands and we can make of it whatever we want to.