McGill scientists are playing a leading role in explaining how the nature vs. nurture debate is even more complicated than we thought.
This article originally appeared in the Spring-Summer 2011 issue of the McGill News
What if your ability to pay the rent, to buy groceries or the nature of your relationships set up your children for cardiovascular problems, diabetes or even mental health issues? Although it’s not a far-fetched idea, researchers struggled for years to find biological explanations that linked socioeconomic status or trauma to health. And then, beginning in 2004, scientists at McGill began to untangle some of those connections.
Piece by piece, study by study, a trio of scientists, backed by a talented crew of post-doctoral fellows, graduate students and research associates, has found evidence that early life experiences can leave lasting marks on the brain. They’ve dismantled the long-standing debate over nature versus nurture, and discovered that it’s not one or the other, but both.
Though the early 2000s were marked by gushing enthusiasm over the sequencing of the human genome and the secrets it would uncover, Michael Meaney, Moshe Szyf and Gustavo Turecki, PhD’99, targeted their study of health and heredity at another level of genetic information. They looked above the genome, at the epigenome, a code of biochemical tags, often attached to DNA, that turn genes on or off.
Their research has run the gamut of experimental design: they’ve studied rodents to understand the impact of maternal care on stress, looked at post-mortem tissue to get at the biological effects of childhood abuse, and are currently following 500 mothers and their children to learn how maternal stress and well-being influence child development. Their group has published in the top scientific journals and their work has been featured in media around the world, including the New York Times, BBC, Time, the Economist, and, more recently, the New Yorker. Together they’ve helped usher into the spotlight this new field of epigenetics and put Montreal at its epicentre.
Getting a good licking
Michael Meaney is a neurobiologist and clinical psychologist who splits his time between the Douglas Mental Health University Institute at McGill and the Singapore Institute for Clinical Science. In his lab, there are two kinds of rat mothers: those that lick and groom their pups and those that don’t. He and his team have found that the well-licked pups are even-tempered critters that produce less of the stress hormone cortisol when faced with a pressure-filled situation. These cool-headed traits persist into adulthood. But Meaney wanted to understand how an environmental signal, such as the nuzzles and caresses of a nurturing mother, could reshape the genome and change the rat’s response to stress.
At a research meeting in Madrid, Meaney encountered Szyf, a molecular biologist and a fellow McGill scientist. The two hadn’t really known each other in Montreal, but as they sipped beer together in a Spanish bar, they launched into an animated discussion about how experiences could leave a lasting mark on the genome and a new research partnership was soon forged.
Szyf, the University’s James McGill professor of pharmacology and therapeutics, has long studied epigenetics in tumour cells—the dynamic modification of the genome through a process called methylation. The pair thought methylation, which alters how genes function, might be the mechanism they were looking for.
Switching the signals
The genetic code is written in letters, each one representing a different chemical: guanine (G), cytosine (C), adenine (A) and thymine (T). Three billion of these letters are strung end to end like patio lanterns, coiled and wrapped around proteins and packed into each cell. The genome is the ultimate insider’s guidebook to the human: it contains all the information a cell needs to produce a neuron, an acid-producing cell in the stomach, or any of the other 200 different cell types crowded into the human body.
But it is the epigenome that provides the directions, revealing which genes should be expressed by adding or removing chemical tags composed of carbon and hydrogen from the genome. A tag planted near a gene will shut it down.
When the researchers looked at the epigenomes of the rats, they found that when a mother licks her pups, she switches on a gene that dials down the amount of stress hormones that get released in times of duress. Meaney and Szyf had found a mechanism to link environmental cues and gene expression.
It was an unconventional conclusion. Though scientists have known about these tags for some time, many thought their role was restricted to cell differentiation, the process that ensures that, for example, a heart cell remains a heart cell when it divides by expressing only the genes a heart cell requires. Instead, Meaney and Szyf, working with graduate student Ian Weaver, PhD’06, and their team, found evidence that life experiences alter DNA by painting it with chemical tags and altering nearby gene expression.
They also showed that they could remove the stress-related methylation by putting unlicked pups with nurturing foster-mothers, or by injecting a drug called trichostatin A into the brains of adult rats—in effect erasing the negative effects of early life experiences.
They submitted the study to Nature and Science and elsewhere. “We got mixed responses. Some were really excited, others were really skeptical,” says Szyf. The reviewers took issue with the idea that such epigenetic changes could occur after birth. How could a complex system that made sure your eye was always an eye also be manipulated by motherly love? Szyf speculates that the system has a highly organized component that is very strict, “and can’t be messed up,” and a responsive component that allows the system to adapt. The study was finally published in Nature Neuroscience in 2004, and it made a huge splash.
One of the scientists who took note was Gustavo Turecki. “The nature vs. nurture debate has been very divisive and created very strong rivalries between the different factions, dividing psychiatry departments,” he says.
A psychiatrist and the director of the McGill Group for Suicide Studies, Turecki approached Meaney after hearing him speak about his research at a scientific meeting. Turecki, who is also the director of the Réseau Québécois de recherche sur le suicide, had access to the Quebec Suicide Brain Bank, an almost unique resource for scientists keen on understanding the neurobiology of suicide.
In 2005, Patrick McGowan joined Meaney’s lab as a postdoctoral fellow after finishing his PhD at Duke University. He’d jumped at the chance to come back to Montreal (he’d obtained his undergraduate degree from Concordia) and to work with Meaney in the field of epigenetics. “I was interested in the epigenetics story from the beginning. It had always been an interesting question: Why do these effects of early life experiences persist? And why do [traumatic experiences] lead to an increased risk for mental disorders? There hadn’t really been a good explanation, but epigenetics offered the first clues as to how that can happen,” says McGowan.
McGowan thought that when he joined Meaney’s lab he’d be working with animals, where his background lay. Instead, because of Turecki’s involvement, McGowan found himself examining human tissue. “Humans are so variable. A lot of people asked, ‘How could you possibly pull out the effects of early life experiences?’” he says. “We had to find the right population, the right cohort, and with Gustavo Turecki’s subjects, we had that. These people had committed suicide. [We] also had the life histories of these individuals and [we knew] they’d suffered terrible, terrible experiences.”
McGowan identified 36 brain tissue samples for the study. They came from men who had been abused as children and who had later committed suicide, and men who had committed suicide, but had no history of abuse. The last group came from otherwise healthy men and made up the control group.
The researchers chose to focus on the stress response genes that are expressed in the hippocampus, one of the brain structures involved in anxiety, depression, placing events in place and time, and storing long-term memories. The researchers discovered something consistent among the suicide victims who had troubled pasts. They found methyl groups fixed to the genes that control the production of stress hormone receptors in the brain, making these individuals far more biologically sensitive to stress.
“What we did was pretty cool. It might take us somewhere that lets us understand why the genome operates differently in one individual versus another, and why environmental events might explain that,” says Meaney.
In 2003, Meaney and other investigators began recruiting pregnant women to participate in the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project. They enrolled 500 women, some of whom suffered from depression or lived in poverty. They visited the mothers to evaluate the type of stressors they faced: Did they have enough money to pay for rent, or buy food for the family? Were they in a violent relationship? What sort of social support did they have? And they followed the children from birth, checking in at three, six, 12, 18 and 24 months, and every year after until they turned eight. The researchers did a battery of tests, measuring cognitive and physical development, attention, food preferences and mother-child interaction. They measured hormone levels and collected DNA.
“MAVAN is unique in Canada,” says Hélène Gaudreau, MAVAN’s study coordinator.
A question of confidence
The study is ongoing, so few of the results have been published. Part of the project measures the kids’ confidence and compares it to their genetic backgrounds and upbringing. Generally, a child’s confidence level drops following the experiencing of a failure. But what Meaney and Gaudreau have found is that genetics and maternal care combine to determine whether confidence plummets or only dips following failure.
The serotonin transporter is one of the proteins associated with emotion. Individuals who possess a shorter version of the gene are at a greater risk of developing depression. But genetics alone can’t predict which children will be most upset when they fail a test. It also depends on the child’s attachment to his mother, they discovered. The study found that those with the shorter gene avoided the emotional crash if they were cuddled and cooed over, and formed a strong bond with their mothers.
“There are two points to this: one is the interdependence of genes and environment, and the other is that your genes don’t make you sick. They make us more or less susceptible to environmental influences. It’s a much more sophisticated way of thinking about what genes do,” says Meaney.
“Hopefully, we’ll be able to see which children are more sensitive to developing vulnerabilities, and we can find a way to help those families,” says Gaudreau. “A lot of people talk about maternal stress and its impact on the baby. But it’s not fixed—you can reverse some of those effects and that is good news.”
Over the last decade, Montreal has become an epigenetics hotspot. In addition to the MAVAN study, Meaney continues to study rodents, taking a broader look at the genome to understand whether particular types of genes are more vulnerable to the maternal influence than others. Szyf recently received funding through a European neurosciences and mental illness research network to study the effects of prenatal, perinatal and postnatal stress and its epigenetic impacts on depression. McGowan, who is now an assistant professor in biological science at University of Toronto Scarborough, is collaborating with Szyf and researchers at Université de Montréal and Université Laval on a study of twins that will examine such things as parenting behaviour and family functioning. The study could help explain how environmental factors affect early mental health development. McGowan is also preparing to teach a university-level course in epigenetics, introducing the next generation of scientists to a field he helped pioneer.