Globe & Mail (Toronto, Ontario), March 11, 2006


[Rachel's introduction: Scientists are still deciphering what has been described as the second genetic code. They know that a number of chemicals in our bodies act like dimming switches. They suspect this chemical switching system can be affected by diet, the air pollution we inhale, whether we smoke, and the stress we endure -- and the resulting changes can be passed along to offspring.]

By Anne Mcilroy

Scientists are rewriting the laws of heredity as they learn more about a mysterious second genetic code that turns our genes on and off.

The traditional idea that we are the passive carriers of our genes is being challenged by the notion that we are their custodians. Our lifestyles -- what we eat, how much we exercise, whether we smoke -- may play a role in a chemical switching system that activates or deactivates our genes. There are signs that our behaviour may program sections of our children's DNA, and that how we live may even affect our grandchildren's genes.

"It introduces the concept of responsibility into genetics," said Dr. Moshe Szyf, a researcher at McGill University in Montreal and a pioneer in the field of epigenetics, the study of genetic changes that don't involve mutations in DNA.

"It changes the whole way we think about inheritance."

If DNA is the hardware of inheritance, the epigenetic operating system is the software, controlling the 30,000 genes that carry instructions for the proteins that make up our bodies and keep them running.

Scientists are still deciphering what has been described as the second genetic code. They know, Dr. Szyf said, that a number of chemicals in our bodies act like dimming switches and determine whether every gene in each cell produces a lot of a particular protein, very little or none of it.

They suspect this chemical switching system can be affected by diet, the air pollution we inhale, whether we smoke, and the stress we endure. It may be a mechanism through which our environment affects our genes.

In mice there is proof some of these changes can be passed down from generation to generation. There are signs this may be the case for humans, as well, if the environmental changes affect genes in sperm or eggs.

A recent study found that found men who started smoking before puberty are more likely to have overweight male children. Dutch women who went hungry in the Second World War gave birth to small babies, but their children also had small babies, even though they had enough to eat.

There is also evidence, at least in rats, that a mother can turn genes on and off in her offspring. Mothers who lick their pups activate a gene that restricts the production of the stress hormone cortisol. As a result, their babies are more laid back.

Canadians scientists in Montreal and Hamilton are now doing an unprecedented experiment in humans, and want to find whether a mother's behaviour affects similar genes in young children. They should have preliminary results by the fall.

A recent study in Spain found that as identical twins get older, they become genetically less similar. They start out with the same genes, but as they age, the switches that control their genes start to look different. The changes are barely noticeable in three-year-old twins, and most pronounced in elderly twins, especially those who have spent less of their lives together.

This helps explain why, in the Spanish study, a 35-year-old woman developed breast cancer but her identical twin didn't. It may also explain why when one identical twin develops schizophrenia, it is estimated that the other one has only a 50-per-cent chance of developing the mental illness.

Pamela Spiro Wagner started hearing voices the day John F. Kennedy was assassinated. Carolyn Spiro, her identical twin, became a psychiatrist. She was on call at a Boston hospital when her sister was admitted in a catatonic state, one arm extended into the air.

"This can't be my twin," she recalls thinking at the time. The two wrote a memoir, published last year, called Divided Minds: Twin Sisters and their Journey through Schizophrenia.

Identical twins can look less similar as they get older, and often act very differently. Epigenetics may help explain why.

Connie Millar, 31, says she began noticing more physical differences between herself and identical twin Kendra four or five years ago.

The sisters share a home in Welland, Ont.

"My hair is nice and full," Connie said. Kendra, younger by 11 minutes, conceded her hair is little thinner.

"Hers is more curly."

Their noses are a little different. Connie's turns up a little more, Kendra said. Connie weighs about 30 pounds less than her twin, and likes to curl and dance and go to the racetrack. Kendra is more of a homebody, and is fascinated by royalty.

Darrick Antell, a plastic surgeon in Manhattan, began doing face lifts on identical twins so he could compare the two surgical techniques. But he found that one twin was always an older version of the other. Smoking, sun exposure, diet and the amount of stress they had endured took a toll on their faces. But some of the differences were not so easily explained. One set of twins lived together, but one smoked and the other didn't. The smoker had much more grey hair than his twin.

"I think there is more at work here," said Dr. Antell, who has performed plastic surgery on more than 30 sets of twins, more than anyone else in the world.

But epigenetics may help explain more than the differences between people who are genetically identical.

Scientists are also looking at many common diseases to see if they might be caused, at least in part, by problems with the switching system that activates and deactivates genes. In Canada and around the world researchers are looking at the role epigenetics plays in various kinds of cancer, schizophrenia, bipolar disorder, Parkinson's disease, Alzheimer's disease, lupus and other illnesses.

Genes seem to play a part in all of these diseases, but not always the starring role. One patient with Alzheimer's can't recognize the faces of their loved ones, while someone else with the same gene linked to the disease is lucid at the age of 90.

The difference is not a mutation, or a change to the four chemicals -- known as nucleotides -- that make up the long strings of DNA in our chromosomes that we inherited from our parents. The problem may be an aberration in the operating system that controls which genes are turned on and off, and how much protein they produce.

In a number of kinds of cancer, a gene that suppresses tumour growth appears to get turned off, Dr. Szyf said. He and his colleagues believe they have discovered a way to turn it on again, with one of two epigenetic cancer drugs now being tested in clinical trials by the Montreal company MethylGene.

They aren't alone. Researchers say dozens of new epigenetic cancer drugs are now being tested around the world, almost all attempting to turn on genes that stop the growth of tumours. One, azacitidine or Vidaza, has been approved in the United States, but not yet in Canada. So far, however, it is not a miracle drug. It appears to help 16 per cent of those who take it.

Dr. Szyf is also exploring what role the switching system plays when cancer metastasizes, or spreads from the original site to other parts of the body.

He is also interested in the role gene switches play in behaviour, including suicide. He is working on epigenetic profiles of men who committed suicide, studying cells from their brains to see if there is a pattern in the genes that are turned on or off. So far, he has studied cells from 14 men who killed themselves, and says the preliminary results are promising.

Arturas Petronis, at the Centre for Addiction and Mental Health in Toronto, is working on the epigenetic profiles of both schizophrenia and bipolar disorder, which used to be known as manic depression. He is studying the brain cells of people with those mental illnesses who died, and comparing them with cells from the brains of people who didn't have either disease. He is looking for a pattern of on-off switches that is distinctive in schizophrenia and in bipolar disorder.

There is no evidence that lifestyle factors -- like drug use -- play a role in switching genes on or off in people who suffer from mental illness. Neither is there proof that lifestyle causes epigenetic changes that lead to other diseases, like cancer. But it may that be that smoking, for example, alters the activity of genes in lung cells.

Dr. Petronis characterizes the epigenetics explanation as a promising theory, one that may answer many perplexing questions about cancer and other diseases.

But first, he and other researchers caution, many mysteries need to be solved. No one knows how the switches in all our cells are controlled. Also unknown is to what extent changes in them are passed down from generation to generation.

Some researchers, however, believe epigenetics holds enormous promise for treating disease. It may be possible -- eventually -- to turn genes on or off, to increase or decrease the production of protein that is part of a disease. It may prove easier than conventional gene therapy, where new genes are inserted into a patient's genetic code.

"Epigenetics will completely change the face of medicine," Dr. Szyf predicted.

It also may change the way we think about pollution, or the chemicals in many products we use every day.

A number of scientists suspect that heavy metals, pesticides, diesel exhaust and tobacco smoke and other chemicals in the environment may be interfering with the human genetic switches. They fear that endocrine disrupters, the so-called gender-bender chemicals, may somehow be switching genes on and off, resulting in fish with both male and female sexual organs and male alligators with shrinking penises.

Michael Skinner a professor at Washington State University, briefly exposed pregnant rats to high levels of two endocrine disrupters, and insecticide and a fungicide. He and his colleagues found that their male offspring had lower fertility and sperm production for not one, but four generations.

Dr. Syzf said that in the future, chemicals should be evaluated not only for whether they cause changes to DNA, but whether they affect the amount of protein a gene produces.

He is working on a way to do this, and said the first step is to identify the sites in the genome that are most vulnerable to these changes.

Scientists are also intrigued about the role epigenetics may play in evolution. Switching genes on and off may be a way for animals, including humans, to adapt to the environment more rapidly than the glacial speed allowed by evolution, which depends on relatively rare mutations to DNA.

"You inherit DNA, but it doesn't tell you if you are living in a rich or a poor environment. If it is rich, you don't have to store fat, don't need to be anxious," Dr. Szyf said. "But if you are going to be thrown in a ghetto, that is a different thing."

Take the mother rats that don't lick their pups much. They tend to be at the low end of the rat social hierarchy, and as a result lead more stressful lives. It is probably a good thing that their pups produce more cortisol -- a stress hormone -- and are more uptight. Cortisol makes rats less aggressive, and less likely to get into fights they can't win.

Researchers in Montreal have found that the boys in neighbourhoods with high crime rates who don't get in much trouble tend to have higher levels of cortisol than boys who join gangs or steal cars. Their higher stress level seems to make them more fearful, and less likely to engage in risky business.

As for our modern lifestyles, exercise is good, but not just for burning calories. It may reprogram our genes, Dr. Szyf said.

Fat may do more than add extra body weight and clog arteries; it may also switch a number of genes on and off that in the past were helpful in preparing humans for a long winter without much food.

Epigenetics may revolutionize medicine, said Dr. Szyf, and it also could change the way we think about daily decisions like whether or not to order fries with a meal, or to go for a walk or to stay in front of the television. You aren't eating and exercising for yourself, but for your lineage.

Loosening the strands of DNA

Flicking genes on and off.

It would mean chaos -- and probably death -- if every gene in every cell of our body were active at once. Brain cells would get clogged with the proteins the kidneys, liver, heart, lungs and skin need to function, and vice versa.

The body needs a way to orchestrate our genes -- especially when an embryo is developing. Scientists are learning more about the chemical switching system that determines what genes get turned on or off, and when.

Most genes carry instructions about what cells they will be used in, says Tom Hudson, a researcher at McGill University in Montreal. But they still need to be activated or deactivated.

Scientists know that for easy storage, the DNA in cells is tightly wrapped around blocks that are called histone proteins. Think of string around a grapefruit, says Michael Meaney, a McGill researcher who found that mother rats can turn a gene on in their pups by frequently licking them.

For a gene to work, and make a protein, the string has to loosen, or the grapefruit has to move or change shape. So far, scientists know of at least five ways this happens, and are exploring how the different chemical reactions that turn genes on and off may be linked. The process they perhaps understand the best is called methylation, in which chemical tags are added to the DNA, tightening the string around the grapefruit so that a gene is silenced, or partially silenced.

Scientists are now mapping these tags, much as they mapped the human genome. They are marshalling resources for an international effort, similar to the human genome project. So far, scientists have mapped the differences in 25 genes that suppress the growth of tumours, says Manel Esteller, a Spanish researcher who did an experiment that showed identical twins become less genetically similar as they age.

They say the human epigenome project will produce profiles of diseases, a map that would show which genes are turned on or off in people with various forms of cancer, as opposed to people who don't get the disease.

Canadian researchers are working on their own on similar epigenetic profiles of schizophrenia, bipolar disorder and other diseases.

It most cases, it seems that epigenetic changes are not passed from parents to their offspring. Scientists aren't sure how -- but genes seems to be wiped clean after a sperm fertilizes an egg.

But they are intrigued by the notion that some changes may be passed on from generation to generation, and may be influenced by our diet or behaviour.

There is proof this sometimes happens in plants, yeast flies and mammals. Researchers in Australia and the U.S can get yellow mice to have brown babies if they feed them nutritional supplements like folic acid and vitamin B12 during pregnancy. But genetically identical yellow mice not given the supplements had yellow babies.

All of the animals had the same gene that helps determine fur colour, known as the Agouti gene. But in the mothers who were fed the dietary supplement -- and their babies -- the gene had extra chemical tags attached. It was methylated, and produced much less of the protein that colours mouse hair.

It has not been proven that changes to the epigenetic switching can be passed from generation to generation like this in humans, but there are signs it may happen, especially as it relates to diet. Swedish researcher Gunnar Kaati and his colleagues have looked at records from 1890 to 1920. They found that boys who matured in times of plenty had grandchildren with a higher rate of diabetes.

Copyright Copyright 2006 Bell Globemedia Publishing Inc.