Globe & Mail (Toronto, Ontario)  [Printer-friendly version]
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

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

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

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

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

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

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.