The 19th and 20th 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 7th
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