The Epigenetics Revolution Quotes

“Our brains contain one hundred billion nerve cells (neurons). Each neuron makes links with ten thousand other neurons to form an incredible three dimensional grid. This grid therefore contains a thousand trillion connections - that's 1,000,000,000,000,000 (a quadrillion). It's hard to imagine this, so let's visualise each connection as a disc that's 1mm thick. Stack up the quadrillion discs on top of each other and they will reach the sun (which is ninety-three million miles from the earth) and back, three times over.”
― Nessa Carey, The Epigenetics Revolution

“But DNA isn’t really like that. It’s more like a script. Think of Romeo and Juliet, for example. In 1936 George Cukor directed Leslie Howard and Norma Shearer in a film version. Sixty years later Baz Luhrmann directed Leonardo DiCaprio and Claire Danes in another movie version of this play. Both productions used Shakespeare’s script, yet the two movies are entirely different. Identical starting points, different outcomes.”
― Nessa Carey, The Epigenetics Revolution

“Sometimes the greatest scientific breakthroughs happen because someone ignores the prevailing pessimism.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“It’s not just humans who have trisomies of the sex chromosomes. One day you may be happily amazing your friends with your confident statement that their tortoiseshell cat is female when they deflate you by telling you that their pet has been sexed by the vet and is actually a Tom. At this point, smile smugly and then say ‘Oh, in that case he’s karyotypically abnormal. He has an XXY karyotype, rather than XY’. And if you’re feeling particularly mean, you can tell them that Tom is infertile. That should shut them up.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“To see what everyone else has seen but to think what nobody else has thought”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance

“It’s incredible to think that mammalian cells carry about 20,000 genes, and yet it only takes four to turn a fully differentiated cell into something that is pluripotent.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance

“The epigenetics revolution is underway.”
― Nessa Carey, The Epigenetics Revolution

“You could make iPS cells by introducing just four genes into a differentiated cell.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance

“Children who eat breakfast are statistically more likely to do well at school than children who skip breakfast.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance

“Given that the modification is so small, it’s perhaps surprising that it will come up over and over again in this book, and in any discussion of epigenetics. This is because methylation of DNA has profound effects on how genes are expressed, and ultimately on cellular, tissue and whole-body functions.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance

“This means that even if cells have accumulated potentially dangerous epigenetic changes, these will be removed before they are passed on.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“Sometimes, when we read about biology, we could be forgiven for thinking that those three letters explain everything.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“The ‘epi’ in epigenetics is derived from Greek and means at, on, to, upon, over or beside. The DNA in our cells is not some pure, unadulterated molecule. Small chemical groups can be added at specific regions of DNA. Our DNA is also smothered in special proteins. These proteins can themselves be covered with additional small chemicals. None of these molecular amendments changes the underlying genetic code. But adding these chemical groups to the DNA, or to the associated proteins, or removing them, changes the expression of nearby genes. These changes in gene expression alter the functions of cells, and the very nature of the cells themselves. Sometimes, if these patterns of chemical modifications are put on or taken off at a critical period in development, the pattern can be set for the rest of our lives,”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance

“Events that take place in the first three months of development, a stage when the foetus is really very small, can affect an individual for the rest of their life.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance

“The histone acetylation levels in the hippocampus and cortex were increased in the mice in the more entertaining surroundings.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“Most of the time these enzymes will only add a methyl group to a C that is followed by a G. C followed by G is known as CpG.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance

“He has shown that these poised histone modifications are found in early cancer stem cells and are really significant for setting the DNA methylation patterns in cancer cells”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“What holds cells in this teetering position? In 2006, a group headed by Eric Lander at the Broad Institute in Boston, found at least part of the answer. A key set of genes in ES cells, the pluripotent cells we have come to know so well, were found to have a really strange histone modification pattern. These were genes that were very important for controlling if an ES cell stayed pluripotent, or differentiated. Histone H3K4 was methylated at these genes, which normally is associated with switching on gene expression. H3K27 was also methylated. This is normally associated with switching off gene expression. So, which modification would turn out to be stronger? Would the genes be switched on or off? The answer turned out to be both. Or neither, depending on which way we look at it. These genes were in a state called ‘poised’. Given the slightest encouragement – a change in culture conditions that pushed cells towards differentiation for example – one or other of these methylations was lost. The gene was fully switched on, or strongly repressed, depending on the epigenetic modification”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“In our model, treatment with 5-azacytidine will drive down the DNA methylation for as long as the patients take the drug. Unfortunately, many cancer drugs have serious side-effects and the DNMT inhibitors are no exception. The side effects may eventually become such a problem that the patient has to stop taking the drug. However, the patient’s cancer cells probably still have histone modifications at the tumour suppressor genes. Once the patient stops taking 5-azacytidine, these histone modifications almost certainly start to attract the DNMT enzymes all over again, re-initiating stable repression of gene expression.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“In this model, there is a vicious cycle of events that results in the generation of a more and more repressed state. One of the predictions from this model is that repressive histone modifications attract DNA methyltransferases, which deposit DNA methylation near those histones. This methylation in turn attracts more repressive histone modifying enzymes, creating a self-perpetuating cycle that leads to an increasingly hostile region for gene expression. Experimental data suggest that in many cases this model seems to be right. Repressive histone modifications can act as the bait to attract DNA methylation to the promoter of a tumour suppressor gene. A key example of this is an epigenetic enzyme we met in the previous chapter, called EZH2. The EZH2 protein adds methyl groups to the lysine amino acid at position 27 on histone H3. This amino acid is known as H3K27. K is the single letter code for lysine (L is the code for a different amino acid called leucine).”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“It’s abundantly clear that these events do happen, and quite frequently, but often it’s been difficult to identify exactly how a tumour suppressor has mutated. In the last fifteen years, we’ve started to realise that there is another way that a tumour suppressor gene can become inactivated. The gene may be silenced epigenetically. If the DNA at the promoter becomes excessively methylated or the histones are covered in repressive modifications, the tumour suppressor will be switched off. The gene has been inactivated without changing the underlying blueprint.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“So there is a consistent finding. Our two unrelated compounds, which control growth of cancer cells in culture and which have now been licensed for use in human treatment, inhibit epigenetic enzymes. In doing so, they both drive up gene expression which raises the obvious question of why this is useful for treating cancer. To understand this, we need to get to grips with some cancer biology.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“But if dividing cells are treated with 5-azacytidine, this abnormal cytidine base is added into the new strand of DNA as the genome gets copied. Because the abnormal base contains a nitrogen atom instead of a carbon atom, the DNMT1 enzyme can’t replace the missing methyl group. If this continues as the cells keep dividing, the DNA methylation begins to get diluted out.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“Pharmaceutical companies became very interested in using siRNAs as potential new drugs. Theoretically, siRNA molecules could be used to knock down expression of any protein that was believed to be harmful in a disease. In the same year that Fire and Mello were awarded their Nobel Prize, the giant pharmaceutical company Merck paid over one billion US dollars for a siRNA company in California called Sirna Therapeutics. Other large pharmaceutical companies have also invested heavily. But in 2010 a bit of a chill breeze began to drift through the pharmaceutical industry. Roche, the giant Swiss company, announced that it was stopping its siRNA programmes, despite having spent more than $500 million on them over three years. Its neighbouring Swiss corporation, Novartis, pulled out of a collaboration with a siRNA company called Alnylam in Massachusetts. There are still plenty of other companies who have stayed in this particular game, but it would probably be fair to say there’s a bit more nervousness around this technology than in the past. One of the major problems with using this kind of approach therapeutically may sound rather mundane. Nucleic acids, such as DNA and RNA, are just difficult to turn into good drugs. Most good existing drugs – ibuprofen, Viagra, anti-histamines – have certain characteristics in common. You can swallow them, they get across your gut wall, they get distributed around your body, they don’t get destroyed too quickly by your liver, they get taken up by cells, and they work their effects on the molecules in or on the cells. Those all sound like really simple things, but they’re often the most difficult things to get right when developing a new drug. Companies will spend tens of millions of dollars – at least – getting this bit right, and it is still a surprisingly hit-and-miss process. It’s so much worse when trying to create drugs around nucleic acids. This is partly because of their size. An average siRNA molecule is over 50 times larger than a drug like ibuprofen. When creating drugs (especially ones to be taken orally rather than injected) the general rule is, the smaller the better. The larger a drug is, the greater the problems with getting high enough doses into patients, and keeping them in the body for long enough. This may be why a company like Roche has decided it can spend its money more effectively elsewhere. This doesn’t mean that siRNA won’t ever work in the treatment of illnesses, it’s just quite high risk as a business venture.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“Tourette’s syndrome is a neurodevelopmental disorder where the patient frequently suffers from involuntary convulsive movements (tics) which in some cases are associated with involuntary swearing. Two unrelated individuals with this disorder were shown to have the same single base change in the 3′ UTR of a gene called SLITRK139. SLITRK1 appears to be required for neuronal development. The base change in the Tourette’s patients introduced a binding site for a short ncRNA called miR-189. This suggests that SLITRK1 expression may be abnormally down-regulated via such binding, at critical points in development. This alteration is only present in a few cases of Tourette’s but raises the tantalising suggestion that mis-regulation of miRNA binding sites in other neuronal genes may be involved in other patients.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“There is a small ncRNA called BC1 which is expressed in specific neurons in mice. When researchers at the University of Munster in Germany deleted this ncRNA, the mice seemed fine. But then the scientists moved the mutant animals from the very controlled laboratory setting into a more natural environment. Under these conditions, it became clear that the mutants were not the same as normal mice. They were reluctant to explore their surroundings and were anxious37. If they had simply been left in their cages, we would never have appreciated that loss of the BC1 ncRNA actually had a quite pronounced effect on behaviour. A clear case of what we see being dependent on how we look.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“But if ncRNAs are so important for cellular function, surely we would expect to find that sometimes diseases are caused by problems with them. Shouldn’t there be lots of examples where defects in production or expression of ncRNAs lead to clinical disorders, aside from the imprinting or X inactivation conditions? Well, yes and no. Because these ncRNAs are predominantly regulatory molecules, acting in networks that are rich in compensatory mechanisms, defects may only have relatively subtle impacts. The problem this creates experimentally is that most genetic screens are good at detecting the major phenotypes caused by mutations in proteins, but may not be so useful for more subtle effects.”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“ncRNAs have recently been implicated in Lamarckian transmission of inherited characteristics. In one example, fertilised mouse eggs were injected with a miRNA which targeted a key gene involved in growth of heart tissue. The mice which developed from these eggs had enlarged hearts (cardiac hypertrophy) suggesting that the early injection of the miRNA disturbed the normal developmental processes. Remarkably, the offspring of these mice also had a high frequency of cardiac hypertrophy. This was apparently because the abnormal expression of the miRNA was recreated during generation of sperm in these mice. There was no change in the DNA code of the mice, so this was a clear case of a miRNA driving epigenetic inheritance”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“But some mRNAs can take a long time to break down in a cell. This means that when a stem cell starts to differentiate, there will be a period when it still contains many of the stem cell mRNAs. Happily, when the stem cell starts differentiating, it switches on a new set of miRNAs. These target the residual stem cell mRNAs and accelerate their destruction. This rapid degradation of the pre-existing mRNAs ensures that the cell moves into a differentiated state as quickly and irreversibly as possible”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance

“miRNAs play major roles in control of pluripotency and control of cellular differentiation. ES cells can be encouraged to differentiate into other cell types by changing the culture conditions in which they’re grown. When they begin to differentiate, it’s essential that ES cells switch off the gene expression pathways that normally allow them to keep producing additional ES cells (self-renewal). There is a miRNA family called let-7 which is essential for this switch-off process”
― Nessa Carey, The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance