Gene therapy, the natural way

Photo: John Lehmann

Researchers are investigating whether the touch
of an attentive mother such as Winnie Chiu in

Vancouver
can cause beneficial genes to 'swtich
on' in her baby, James John Hin Lehmann.

By Anne McIlroy
Monday April 5th 2004
Globe and Mail

To an infant, a mother's touch is warm and comforting. Now a Canadian researcher has found out how it can also trigger profound changes beneath the skin how a caregiver's touch can physically alter a baby's genes. McGill University's Michael Meaney's revolutionary findings may finally end the long debate over whether heredity or the environment play the primary role in shaping an individual's personality.

The nature-nurture debate has become less fierce in recent years: Many scientists now accept that a mysterious dance between genes and environment determines who we become. Dr. Meaney and his colleagues have uncovered an important step in that dance, by showing for the first time how conditioning can change the chemical structure of the genes we inherit in effect, switching them on or off.

Their work is with rats. But his team has just begun a $4-million, five-year study that could be the first in the world to confirm that it also applies to humans.

There are two different kinds of rat mothers those that lick their pups a lot and those that don't. Dr. Meaney found that, under provocation, the high-licking mothers' offspring produced less of the stress hormone cortisol. They are more stable individuals that are not as easily panicked.

Picture half a dozen rats in a cage, eating. Dr. Meaney claps his hands loudly, and all the animals freeze. Some rats almost immediately go back to gobbling their food, realizing that the researcher doesn't pose a real threat. But others will remain immobilized for up to 10 minutes, and may never go back their lunch. The difference? The timid rats are the offspring of mothers who didn't lick them much.

How can licking make that much of a difference in personality is it due to their genes, or the way they were raised? The answer is both. In essence, the high-licking moms produce changes in their babies' DNA. Their pink tongues somehow flick on the same chemical switch that turns genes on and off in a developing embryo.

In the fetus, this process which scientists call methylation allows development of the brain and organs to proceed in an orderly fashion. In the baby rats, the high-licking mothers somehow switch on a gene that restricts the production of cortisol. The low-licking mothers do not, so their pups produce much higher levels of the stress hormone.

Cortisol helps prepare the body to deal with a threat -- such as the possibility that a clapping researcher means them harm. In short bursts, it can save an animal's life. But over the long term, a heightened stress response has been linked to diabetes, heart disease, mental illness and other serious ailments in both humans and lab animals.

"We have now studied that particular gene down to the level where we know what maternal care is doing to turn it on or off," says Dr. Meaney.

He sees his work as helping to reframe the nature-nurture debate, which dates back to at least the 13th century. Extremists on one side have argued that all animal behaviour is instinctive. Hard-liners on the other side have taken the position that experience alone determines behaviour. The argument flares every decade or so, most recently with the mapping of the human genome. Now, the question is no longer whether genes are more important than the environment, says Dr. Meaney. The question is how the environment physically alters genes to produce individual differences.

The genetic changes in the baby rats affected not only the stress response but also cognitive development, since high levels of cortisol inhibits the growth of the hippocampus, a part of the brain involved in memory and learning. Cortisol may also influence how well young animals pay attention. Alison Fleming, a researcher at the University of Toronto, has found that rats brought up without mothers and that don't have attentive researchers stroking them with paint brushes to stimulate licking grow up with more attention problems than animals that get that physical stimulation.

Could the same things be true in humans? We don't regularly lick our babies or stroke them with paint brushes, and Dr. Meaney isn't suggesting that anyone start. His hypothesis is that tactile contact has the same effect. "Mothers don't lick their babies, but they hold them. And they probably tickle them and touch them and stroke them and rub their hair."

There is already indirect evidence that parental care influences how future adults will respond to stress. In one study, young men and women who said their mothers and fathers did a poor job in raising them became much more stressed in an experiment designed to test how they react under pressure. They were asked to perform rapid mental arithmetic problems, and a buzzer would go off every time they were wrong.

Now Dr. Meaney and his number of colleagues across the country are looking for evidence of genetic changes related to human parenting, from touching to more subtle interactions. They want to know how parental care affects genes in human babies.

Does the kind of parents you have influence your genes, causing you to produce different amounts of the proteins involved in stress and learning and behaviour? And do those changes make a major difference in children's lives? Most intriguing to Dr. Meaney is the question of whether early damage can be reversed.

To find answers, they are turning to a group of depressed and pregnant women in Hamilton. Mothers suffering from severe depression often have trouble bonding with the children and tend not to respond as quickly to their cues.

"Some don't bond, some don't bond well. Some of these moms will do the instrumental things, but not the affectionate things. They will feed, bathe, change [diapers]. But there is nothing on their faces," says Dr. Meir Steiner, a McMaster University researcher. "Some women are so irritable, they cannot tolerate the behaviour of the baby, the noise, the crying. They say they want to crawl out of their skin."

In an ambitious experiment called the MAVAN project, for Maternal Adversity Vulnerability and Neurodevelopment, Drs. Steiner, Meaney and others will follow both the depressed mothers and a control group of healthy mothers before they give birth, and closely monitor the moms and their children for more than four years afterwards. The $4-million study is funded by the Canadian Institutes of Health Research.

All of the depressed women will be offered treatment it wouldn't be ethical to withhold it. But past studies have shown that a third are likely not to respond. When the babies are born, they will be tested for 22 genes that may make them vulnerable to aggressive or anti-social behaviour as well as learning disabilities such as attention deficit disorder. Researchers suspect these genes are affected by parental care. Their goal is to find out whether a child with a genetic vulnerability and a depressed mother will get into more trouble than a child with similar genes but with a healthy mother.

Researchers will monitor the children's cognitive and social development for five years. They'll perform brain scans to monitor the physical development of various brain regions. They'll also test the children's cortisol levels.

Most of the concrete data currently available about how a human mother affects the development of her child come from prenatal studies, says Stephen Matthews, a professor of physiology at the University of Toronto and a lead investigator in the MAVAN project. The most obvious example is fetal alcohol syndrome: Babies born to mothers who drank heavily during pregnancy have smaller, less developed brains.

Researchers also know that women who smoke, drink, are highly stressed or are deprived of protein during pregnancy are more likely to give birth to babies with low birth weights. These babies are more prone to a variety of health problems, including high blood pressure, and are more at risk for attention deficit disorder.

The second group that will be studied is in Montreal, selected from a group of 5,000 children who took part in an earlier study on pre-term labour. Some were born with low birth weights, while others were of average size. These children will also undergo genetic tests. The researchers already have reams of data about the mothers' pregnancies, and will go on to monitor how they interact with their children.

These data should show, for example, whether low-birth-weight babies genetically predisposed to attention deficit fare better with attentive mothers than similar children whose mothers are less engaged.

New rat studies in Dr. Meaney's lab certainly offer hope that there will be a difference. Researchers have found that poor maternal care means that a number of genes in the brain involved in memory don't get activated. But if you take those rats including those who are past puberty and put them in an enriched environment, the genes are turned on.

"You really, literally can reverse it," he says.

Not only that, but if you have a female rat pup born to a low-licking mother removed to live with a high-licking surrogate mother, she will become a high-licking mother when she grows up. On the other hand, if a high-licking mother is subjected to high stress, she will pay less attention to her offspring.

However, Dr. Meaney emphasizes that the consequences of less-attentive maternal care may not always be bad. Dr. Meaney's theory is that the low-licking rats are at the bottom of the social hierarchy, and as a result lead more stressful lives. In this situation, helping offspring develop a strong response to stress may be a good thing. For example, the extra cortisol makes the animals less aggressive and so less likely to get into fights. It may be nature's way of helping the animals adapt to their future environment.

In human studies, researchers in Montreal have found that in poorer neighbourhoods with high crime rates, the boys who don't get into much trouble actually have higher levels of cortisol than boys who join gangs and begin stealing cars. Their stress levels seem to make them more fearful and less likely to partake in risky business.

There are many other examples in the natural world of organisms preparing their offspring for the specific environmental challenges they will face. Radishes that are harassed by caterpillars produce chemicals that are toxic to the insects, and grow spines on their leaves. Plants that come from those radishes' seeds will also have spiny leaves, and high levels of the toxic chemicals.

"We are looking at something that happens pretty generally across all biology," says Dr. Meaney. "Nature didn't rip up the blueprint when it got to us."

Much remains unknown, but Dr. Meaney believes the mechanism he identified in the gene that restricts cortisol production in rats is the same one at work in all cases where a parent influences the expression of a gene. His work is part of the burgeoning field of epigenetics the study of changes to genetic material that don't involve altering the sequence of the four nucleotides C, G, T and A that make up our genetic code.

"The whole world knows it really isn't just a question of genes, or just a question of environment," says Dr. Meaney. "It is the interaction between the two of them. Fine, it makes sense intuitively, but what does it mean when the environment interacts with the gene. How? That is what we are showing."

Anne McIlroy is The Globe and Mail's science reporter.


Stress test

Researchers have evidence that stress may actually start to harm children in the womb. Among infants and toddlers, high and chronic levels of stress can make learning more difficult, perhaps even shrinking the part of the brain associated with memory. Stress may also make kids fat.

Experts say the following may be signs a child is unduly stressed. If the problem persists more than a few weeks, medical assistance may be in order.

Physical problems: Stomach trouble, headaches or difficulty falling asleep can be signs of childhood stress.

Worrying out loud: A stressed youngster may seek continual reassurance, and ask parents repeatedly about hypothetical disasters (for instance, their divorce or death).

Avoiding situations: If children don't want to go to class or shun after-school activities, it may be because they find those environments overly stressful.
Anne McIlroy


Mother nature

Can parents help their offspring adapt to the particular environment they will face? Plants and animals do. The illustration is on the Education home page, did you see it?

Radishes

When infested by caterpillars; radish plants grow spiny leaves and produce a natural insecticide. The seeds will produce radishes that already have those defences.

Skink lizards

If you expose a skink to the smell of its predators, a snake, it will become hypersensitive to that smell. The offspring of that skink will be four times more sensitive to the smell of snake than their skink babies

Rats

Rat pups born to mothers that do not lick them very much develop high levels of the stress hormone, cortisol. Researchers suspect these rats are born into a lower status in the social hierarchy and a strong stress response may help them avoid dangerous confrontations.

Education