Epigenetics: A New Vision for Treating Disease

The 19^th and 20^th century saw some huge milestones in our understanding of genes and inheritance, including evolutionary theory, Mendelian genetics, the discovery of DNA and the sequencing of the human genome. These are undeniably huge advancements that have transformed our view of how organisms work and have paved the way to many new treatments of genetic diseases.

But now, a new, rapidly expanding field is turning heads in the scientific community. Because it turns out that the mere sequence of bases (A, C, T and G) in our DNA isn’t the whole story. Epigenetics is the study of how chemical changes to our DNA can alter the expression of genes and, ultimately, have drastic effects on our phenotypes[1]. In some cases, these epigenetic changes can even be passed on from parent to offspring[2], going against the former strong belief that acquired characteristics cannot be inherited. An understanding of epigenetics could be crucial to treating diseases such as cancer and schizophrenia. As such, it is in society’s interests that scientific attention and funding be directed towards the field of epigenetics.

Let’s first consider the epigenetic basis of schizophrenia. Schizophrenia has a high concordance rate of around 53% among identical twins[1,3] as opposed to around 17% among fraternal twins[1], showing that genetics plays an influential role in its development. However, since the figure falls rather short of 100%, there must be other factors at work than merely a person’s DNA sequence – for identical twins are, at the genetic  level, exactly what they say on the tin: identical! This led scientists to believe that environmental factors must be at work as well[4]. Studies have shown that there are indeed environmental risk factors linked to schizophrenia. These include maternal nutritional deficiency during pregnancy[5], psychosocial stress[4,6] and cannabis use[4].

Hold up – how could a mother’s diet during pregnancy affect the risk of her child suffering from a terrible psychotic illness later in life? The answer lies in epigenetics. Epigenetic changes associated with schizophrenia have been linked to chemical changes to two genes in particular: RELN, which encodes a protein called reelin[3,5,7], thought to be involved in memory formation and brain plasticity[7]; and GAD1, which codes for an enzyme that produces an important neurotransmitter called γ-aminobutyric acid[8] (GABA). The chemical changes include the addition of methyl groups to promoter regions on the genes[1], and the removal of acetyl groups from histones[7], special proteins which associate with DNA and make it more compact[9]. These changes affect gene expression by effectively getting in the way of the molecular machinery that transcribes the genes, and hence cause a decrease in the levels of reelin and GABA in the brain, associated with the awful symptoms of schizophrenia.

Epigenetics is also implicated in many incidences of cancer. Whilst irreversible gene mutations (in which the DNA sequence itself is changed) are often responsible for the loss of control that leads to rapid cell division, scientists are becoming increasingly aware that epigenetic changes can also be the culprit[10]. Certain genes, called tumour suppressor genes, regulate the cell cycle and prevent cells from dividing too rapidly. Some tumour suppressor genes are like police officers that stand guard over the genome: if they detect any suspicious activity that could lead to the growth of a tumour, they will “arrest” the cell to stop it from dividing any further[11]. The cell will then effectively commit suicide (a process called apoptosis[9]).

Tumour suppressor genes may be inactivated by the mechanisms described earlier: the addition of methyl groups to DNA, and modifications to the histone proteins associated with DNA[1,12]. If these genes are no longer expressed, the cell has a massively increased risk of becoming cancerous[11]. Substances that inhibit the enzymes which carry out these epigenetic modifications could therefore lead to new cancer drugs! For example, the compound 5-azacytidine, which blocks the activity of DNA methyltransferases (the enzymes which add methyl groups to DNA), has been shown to treat haematological cancers such as leukaemia[13].

One of the major problems with trying to find cures for cancer is that every cancer case is unique. A treatment that works wonders for one patient could do nothing but worsen matters for another. Developing, trialling and mass-producing new drugs is also an incredibly costly process[1]. However, a better understanding of the epigenetic basis of cancer will undoubtedly open doors to previously unimaginable methods of diagnosis and treatment in the future[12,13].

As illustrated by these cases, epigenetics is clearly an area in which continued research could really accelerate medical progress in the coming decades. I hope to see many novel treatments for diseases such as schizophrenia and cancer arise as a result of research into epigenetics in my own lifetime.

REFERENCES

1. Carey, N. The Epigenetics Revolution: How Modern Biology is Rewriting Our Understanding of Genetics, Disease and Inheritance. 2012, Icon Books Ltd. ISBN: 978-184831-347-7

2. University of Utah: Epigenetics and Inheritance. Learn. Genetics: http://learn.genetics.utah.edu/content/epigenetics/inheritance/

3. Alonzi, A. The Epigenetics of Schizophrenia. 08/12/2014, What is Epigenetics: http://www.whatisepigenetics.com/the-epigenetics-of-schizophrenia/

4.  Svrakic, D.M.; Zorumski, C.F.; Svrakic, N.M; Zwir, I; Cloninger, C.R. Risk architecture of schizophrenia: the role of epigenetics. 0951-7367 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

5. Kirkbride, J.B.; Susser, E.; Kundakovic, M.; Kresovich, J.K.; Smith, G.D.; Relton, C.L. Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects? Epigenomics. 2012 Jun; 4(3): 303–315

6. Horan, W.P. ; Blanchard, J.J. Emotional responses to psychosocial stress in schizophrenia: the role of individual differences in affective traits and coping. Schizophr Res. 2003 Apr 1;60(2-3):271-83.

7. Gavin, D.P.; Sharma, R.P. Histone modifications, DNA methylation, and schizophrenia. Neurosci Biobehav Rev. 2010 May; 34(6): 882–888.

8. Wassef, A.; Baker, J.; Kochan, L.D. GABA and schizophrenia: a review of basic science and clinical studies. J Clin Psychopharmacol. 2003 Dec;23(6):601-40.

9. Purves, W.K.; Sadava, D.; Orians, G.H.; and Heller, H.C. Life, the Science of Biology 7^th edition 2004: Sinauer Associates, Inc., Massachusetts. ISBN: 0-7167-9856-5

10. Verma, M.; Srivastava, S. Epigenetics in cancer: implications for early detection and prevention. Lancet Oncol. 2002 Dec;3(12):755-63.

11. Wolpert, L. How We Live and Why We Die: The Secret Lives of Cells. 01/04/2010. ISBN: 978-0571239122

12. Boumber, Y.; Issa, J.P. Epigenetics in cancer: what’s the future? Oncology (Williston Park). 2011 Mar;25(3):220-6, 228.

13. Lamb, R.  How Epigenetics Works.  13/10/2008: HowStuffWorks.com: http://science.howstuffworks.com/life/genetic/epigenetics.htm