Moshe Szyf, James McGill professor of Pharmacology and Therapeutics

When science and the humanities collide

By Cynthia Lee

While Moshe Szyf has been in the spotlight with his most recent paper (published in Nature Neuroscience) on how early negative life experiences affect people’s genes, his is hardly an overnight success story.

Professor of Pharmacology and Therapeutics, Szyf is both a pioneer of and world leader in the field of epigenetics. His trail-blazing research has proven that while our DNA is pretty much set, external factors such as toxins and even the social environment can trigger a biochemical reaction in the nucleus of the cell that can change the way our genes express themselves. Once stimulated, a group of molecules called a methyl group attaches itself to the control centre of a gene, switching it off completely — altering gene function without altering the DNA sequence.

Born in London, England into a family of observant Orthodox Jews, Szyf began his university studies in Political Science, Jewish Studies, Philosophy and Mysticism at Bar-Ilan University in Israel. Family pressure to study something more “practical” pushed Szyf to transfer to dental school. But Szyf’s heart wasn’t into dentistry and he soon embarked upon a path that would change our understanding of DNA forever. Recently, Szyf sat down with the McGill Reporter to talk epigenetics, religion and what he sees as the funding crisis in Canada.

What is epigenetics?

Epigenetics is best described as the markings on genes that program their function. Genes are inherited and don’t change during a life of an individual and they are identical in all parts of the body. The markings on genes are laid down during gestation but could continue and change during life and change differently in different parts of the body.

And DNA methylation?

DNA methylation is a chemical coating of the genes that programs how the gene functions.

How would you describe your work in a nutshell?

My work bridges the humanities and sciences by showing how the non-physical environment affects our genes. It also emphasizes that we cannot understand biology and medicine without taking into account the social, economic and perhaps even the political environment.  Is cancer just a cellular disease? A problem with bad genes? Humans cannot be reduced to a single cell, and we can’t separate people from their environment.

How did you begin working on DNA methylation?

I began in dental school as I was working on my thesis – I was already interested in DNA methylation when I met Aaron Razin, one of the first scientists to discover DNA methylation about 35 years ago. But I was working on it in a bacteriophage – any one of a number of viruses that infect bacteria. At the time, DNA methylation had no relevance to human health and the human condition, but it’s amazing how relevant it has become.

What was the early reaction to epigenetic research?

When I finished my PhD in biochemistry on what was essentially epigenetics and DNA methylation, I was told that that area of study was “over.” In scientific circles it was being dismissed as “epiphenomena” – not a real thing. My teachers told me that it was “some junk of nature.”

When I met a prominent cancer scientist from MIT I asked him about DNA methylation and cancer. He became angry, insisting that cancer was just a genetic disease. There was a lot of animosity towards people who studied methylation.

But despite the opposition, you continued your line of research?

I always managed to sneak DNA methylation into my work.

At Harvard, where I did my postdoctoral work, I was examining a gene involved in steroid synthesis. I found that it was silenced in cancer of the adrenal glands. I believed the gene was silenced by DNA methylation. This was big! Even though my professor said no, it was a genetic mutation, I proved my theory. This was the first proof that cancer genes are silenced by DNA methylation and not only by genetic mutations. I published the paper, and it got no attention.

How did you get to McGill?

I was looking for a job after four and a half years of postdoctoral work at Harvard Medical School and I wrote letters everywhere around the world, and McGill gave me a good offer. So, I wrote my first NCIC (National Cancer Institute of Canada) grant on DNA methylation in 1989.

In 2003, you and Michael Meaney [Professor, Depts. of Psychiatry and Neurology and Neurosurgery] proved that rat pups that were licked frequently by their mothers produced less stress hormones as adults than pups who got little grooming. How important was that collaboration?

The collaboration extended methylation from cancer to a whole new arena. It shows that what we learned about cancer is not unique but applicable to all areas of medicine, human health and behaviour. Major changes to our bodies can be made not just by chemicals and toxins, but also in the way the social world talks to the hard-wired world.

How did you meet Meaney?

I met Michael in Madrid in a bar as we were both attending the same conference, because you never meet McGill scientists at McGill [laughing].

Can cancer be caused by stress?

I believe it could although we have no evidence yet. The old thinking is very deterministic, that you inherit genes mutated by random chance. But our take is, programmed events in response to clear environmental conditions could also alter the way in which genes function, including those involved in cancer.  However, there is no question that inherited gene mutations cause some cancers.

What’s next for you?

To continue trying to understand the impacts of early life environments on humans and epigenomes. I just returned from Washington, where I attended a meeting aimed at creating an international consortium to begin mapping epigenomes. Genomes are the same in every cell, but epigenomes are moving targets and must be mapped in many different environmental contexts. We want to know how epigenomes are related to disease. We believe that epigenetic mechanisms are common to many diseases and we’re looking for common therapies, drugs and possibly social interventions.

And when you unlock that door?

One day we’ll have very exquisite diagnostic tools to determine who is at risk and also what the environments are that put people at risk and perhaps a tool chest of interventions

and therapeutics based on epigenetics.

What are you most proud of?

I am very proud we have moved cancer from a genetic disease to an epigenetic one.

Tell me about the secret life of a scientist.

Actually it’s quite miserable because you spend a lot of time writing grants you know won’t get funded. So 90 per cent of that time is wasted.

What do you think of research funding in Canada?

Our colleagues in the States, they don’t know what to do with the new stimulus package money. Here, our budgets are continuously being cut. Even if you have the sufficient funds, you need vision on where to invest it. A lot of investment has been made in buildings and equipment, and while those are important, we also need to identify smart people and invest in them.

So, is the future bleak?

No, but there should be a complete restructuring and rethinking from A to Z. We’re patching things up and the system does not have enough money to fund the science we are trying to run. Either we increase the money or reduce the science.

What do you do on days off?

[Laughing] I don’t remember if I’ve had a day like that! I would be reading – philosophy. I am deeply interested in religion – in profound questions like what are the limits of science? Where do philosophy and mysticism step in? The whole evolution vs. creation debate. I love history and the development of cultures. I love medieval readings.

How important is religion to you?

I wake up at 5:30 and give classes in Talmud and I pray. Religion drives my scientific work because it creates excitement about God’s creation. The ancients wrote psalms about it, we do experiments! In science, we get answers to our questions from nature, in philosophy we don’t. Religion and philosophy interface, and when you ask questions, don’t be bound by anything. Stay open to the answer even if the answer is not what you expected.

What was your first job?

Professor! This is my very first and only job.