For Dr. James Davie of the Children’s Hospital Research Institute of Manitoba, each human cell is like a compact disc full of music that never changes, and the field of epigenetics is the CD player that decides which song gets played. He is leading a team of experts in genetics and epigenetics to better understand and diagnose brain injuries caused by exposure to alcohol in the womb.
Fetal alcohol spectrum disorder (FASD) is a term that encompasses a variety of disabilities caused by prenatal exposure to alcohol. Children with FASD may have problems with memory, attention, decision-making and social skills, as well as mental health issues such as depression and addiction. Moreover, they may have difficulty controlling their emotions. Without proper treatment, they may do poorly in school and end up in trouble with the law.
“Let’s say there was a cluster of neurons that never formed because of changes imposed by alcohol during development,” says Dr. Davie. “You can’t get those neurons back. Once the damage is done, you can’t repair it.”
There is limited information on the prevalence of FASD in Canada, but based on data from the U.S., it is estimated that there are about nine cases per 1,000 births. Some populations, such as Indigenous communities, seem to have higher rates of the condition, but any pregnant woman who drinks is at risk of having a child with the disorder.1
Dr. Albert Chudley, who directs the Genetics and Metabolism Program at the Winnipeg Regional Health Authority, led the development of the Canadian guidelines for FASD diagnosis during the 2000s. Early diagnosis is vital for connecting children with appropriate services, but it’s the exception to the rule. Only about 10% of children with FASD show visible signs, according to Dr. Chudley. The vast majority require an expensive battery of tests from specialists to confirm FASD. Due to the high cost of the tests, most people with the condition remain undiagnosed.
Apart from the toll on affected individuals and their families, FASD imposes a huge cost on social, medical and correctional systems. In Alberta, for example, the annual cost of FASD is estimated at $130-$400 million.2 The Canada FASD Research Network estimates total indirect and direct annual costs across the country at $4 billion.3
While researchers agree that exposure to alcohol leads to FASD, there is limited knowledge on how it causes the condition. Researchers are increasingly convinced that the cause of FASD goes beyond genetics, which is where Dr. Davie’s CD player comes in.
Dr. Davie is best known for his research in another area — specifically the epigenetics of cancer. As a graduate student in the 1970s, he was one of several researchers who independently identified how histones – the protein molecules that help package DNA – activate enzymes that help regulate how cells are processed.Footnote4 He showed how turning off a particular enzyme eventually killed cancer cells, a discovery that led to new inhibitor drugs to treat some cancers.
Dr. Davie went on to research strategies to stop these enzymes from stimulating cancer growth. In particular, he has been trying to develop a biomarker – a detectable chemical signal – to identify a person’s risk of breast cancer. Now, with funding from the Canadian Institutes of Health Research (CIHR), Dr. Davie is applying his knowledge of epigenetics to identify an “Epi-Code”, or epigenetic biomarker, for FASD that will enable early diagnosis and intervention.
As leader of this five-year project, he is guiding the work of five teams that are exploring the disorder from various perspectives, both genetic and epigenetic:
- Dr. Mojgan Rastegar is using mice to investigate the effect of alcohol on stem cells in the nervous system, while Dr. Geoff Hicks is identifying epigenetic changes related to nutrition in mice;
- Dr. Abraham Fainsod from Hebrew University in Israel is building on his earlier research, which demonstrated that vitamin A (retinol) can prevent FASD-like malformations in frog embryos;Footnote5
- Dr. Marc Del Bigio is looking at changes in the brains of autopsied children with FASD; and,
- Dr. Brenda Elias is collecting biological samples from First Nations communities, and working with them to identify what needs to happen once a biomarker is developed.
If the teams are successful in identifying a biomarker for FASD, it could be a game-changing discovery for children born with the disease.
“Diagnosis changes lives. With a biomarker, we can identify those kids faster and get them the right care,” says Dr. Chudley.
Dr. Chudley has been working to recruit individuals and families to study the epigenetics of FASD. His efforts are complemented by Dr. Brenda Elias’ work to engage members of Manitoba’s Indigenous communities in the project. An assistant professor at the University of Manitoba’s Department of Community Health Sciences, Dr. Elias is working with the Southeast Resource Development, which represents eight First Nations in the province.
“Brenda has a wonderful history with First Nations groups here, and has built trust with them,” says Dr. Davie.
In partnership with First Nations communities, Dr. Elias is documenting the “social epigenetics” of FASD — all the factors that can affect the expression of the disorder biologically. These range from family make-up, health conditions and behaviours, to the challenges of delivering economic and social services.
Evidence in Action: A win-win proposition
Through “readiness meetings” and a detailed survey to understand the social epigenetics of FASD, the search for a biomarker is already building capacity in First Nations communities. Apart from engaging affected individuals and their families, the Epi-Code project is also working with different levels of government and both Indigenous and non-Indigenous organizations to identify potential areas for collaboration.
“If we do develop a biomarker, we have the right people – policy-makers, government and Aboriginal groups – on board,” says Dr. Davie. “Without that buy-in, even the most relevant research that could make a difference will stay on the shelf.”
Want to know more about the science of epigenetics?
Epigenetics steps in where mapping the human genome left off. Nature says we inherit our genetic make-up or DNA code from our parents. Many believe this code and the genes it represents set the ‘program’ for who we are and what health risks we might possess. Nurture (or epigenetics) says that this program can be ‘hacked’ by life experience, either increasing or decreasing health risks already in our DNA code. Join the experts in a discussion about whether we can control our health destinies by controlling what we eat, drink, breathe, and where we live.
References:
1. Institute of Health Economics, Consensus Statement on Fetal Alcohol Spectrum Disorder (FASD) – Across the Lifespan (2009).
2. Consensus Statement on Fetal Alcohol Spectrum Disorder (FASD) – Across the Lifespan.
3. Stade, Brenda, et al., “The burden of prenatal exposure to alcohol: Measurement of cost,” Journal of FAS International, 4 (2006):e5.
4. Candido, E. Peter, Reeves, Raymond, and Davie, James R., “Sodium butyrate inhibits histone deacetylation in cultured cells,” Cell, 14,1 (1978):105-113.
5. Kot-Leibovich, Hadas, and Fainsod, Abraham, “Ethanol induces embryonic malformations by competing for retinaldehyde dehydrogenase activity during vertebrate gastrulation,” Disease Models and Mechanisms, 2,5-6 (2009):295-305.
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