Studying The Outside Influences On Genes

Dr. Yehudit Bergman is a professor and cancer researcher at Hebrew University Medical School, where she focuses on how epigenetics — changes in gene activity affected by outside influences — affect immune system development, stem cells, inflammation and cancer.

Bergman, who gew up in Tel Aviv, earned her Ph.D. from Weizmann Institute of Science and completed her postdoctoral studies at Stanford University and MIT. She is an elected member of the prestigious European Molecular Biology Organization and a recipient of the Israel Cancer Research Fund (ICRF) seven-year Professorship Grant. She was recently in New York to speak on behalf of ICRF where The Jewish Week caught up with her to discuss her work in cancer research. This is an edited transcript.

Q.: Why did you decide to go into medical research?

A: I didn’t even think about another option. I just liked it and this was what I wanted to do. My father was an accountant and at that time in Israel the bank would pay for my tuition if I would go and study computer science and I said: It is so boring. … My heart was in biology. It always fascinated me. I wanted to understand what is going on.

Your work is in epigenetics. Can you explain what that is?

We have DNA and all the cells in our body contain the same DNA, but some cells express a pigment, like in the eye, and other cells express hemoglobin, like in a blood cell. So how do you do that? You turn a set of genes on in the eye cell and a different set of genes on in a blood cell. And what tells the DNA whether to be on or off is epigenetics.

It’s like an orchestra, and the DNA is like the instruments and the musicians, and the epigenome is like the conductor — It tells the musicians when and where to play. Sometimes it tells the piano to play and not the violin, and other times it tells the violin to play and not the piano. And sometimes it tells the musician to play strong and sometimes low. This is the epigenome. This is what controls the DNA.

Dr. Yehudit Bergman and her team hope their work in epigenetics will lead to better treatments for lung, ovarian and other “solid tumor” cancers. Courtesy of Hebrew University

But the epigenome isn’t set in the same way that genetics are set because it can be changed by outside influences, right?

Exactly. The epigenome can be controlled by lots of signals from the outside: what we eat, what we drink, how we are exercising, are we going through stress periods? All of these things can fit into the epigenome. And that’s why it’s good in a sense because it’s a way that the cells adapt to the environment. And its easier to manipulate than the DNA sequence itself.

What kind of research are you doing regarding the epigenome?

We have several projects in the lab. I’ll tell you about one of them: We wanted to see what are the changes of DNA methylation during inflammation. Inflammation is a known risk for cancer.

What is DNA methylation?

It is a chemical that is attached to one of the building blocks of the DNA, and you can think of it as a stop sign. When it’s there the genes are not expressed. When its not there the genes are expressed. So it helps tell the cells which sets of genes to turn on and what sets of genes to keep silent.

What can you learn from looking at changes in DNA methylation?

We have known for quite some time there are abnormal changes in DNA methylation in cancer. Some areas lose methylation signals and other areas gain methylation signals and it’s just a mess. We know it has a driver role in cancer. So we ask the question whether these changes, abnormal changes in DNA methylation occur in the inflammatory cells. These cells are not cancer; these are just inflamed cells. So we did it using a mouse model and we showed that the inflamed cell has already aberrant DNA methylation there. So way before this cell becomes a cancerous cell, it’s a premalignant cell; it has already undergone these changes of DNA methylation, which we know are not good for you.

What kind of applications could this research have?

You could use this change in DNA methylation as a biomarker. So if you want to see if a tissue that is not cancerous is premalignant, one way to look at it is to look and see if there is abnormal DNA methylation there. That will give an indication whether it’s going on [to become] a bad cancer.

Then we can use it also as a biomarker for distinguishing different kinds of cancer. Because in all of the cancers, or almost all of the cancers, there is a change in DNA methylation, but these changes are a bit different from one cell to the other and you can use this knowledge of which DNA genes (are affected) and when it changed in DNA methylation to tell you which cancer it is.

You can monitor cancer progression by monitoring the DNA methylation. You can also monitor cancer treatment.

How can you monitor cancer treatment?

For instance, if you treat with [an] anti-cancer [technique] and you want to know if you got rid of the cancer cells, then you look at the leftovers and then ask: Do I see this aberrant, damaging DNA methylation in the leftover cells? If the answer is yes, you know that still, there are some cancer cells there but if the answer is no, then you think you have a good chance [of having gotten rid of the cancer cells].

Are there other applications?

The other aspect is therapy. Knowing that changes in DNA methylation occur early on gave people the hope that maybe inhibiting DNA methylation is going to be helpful for the treatment of cancer.

Can you inhibit DNA methylation?

Yes, you can inhibit DNA methylation and there is already a drug that is FDA approved that physicians are using it to help people, and this is mostly for blood cancers.

Anything else on the horizon?

What is also coming up quite recently is a combination of different therapies. And for that I mean treating with inhibitors for DNA methylation together with other anti-cancer treatments; for example, chemotherapy. Another example is this new immunotherapy mode. So treating the cancer with inhibiting DNA methylation and with the immunotherapy gives very good results. And what they think it’s been doing is that the treatment with the inhibition of DNA methylation sensitizes the cancer cells to be more sensitive to the other drug or whatever the other treatment [is] for cancer.

Part of the advancement that we see in implementing the epigenetics treatment is the ability to sequence the DNA — and its not only just sequencing but also the knowing for every building block whether it’s methylated or not.

So, this technology allows everyone to ask very different questions and more in-depth questions. The downside is that its expensive. It is really expensive. And for basic scientists like I am, this is what the ICRF grant, for example, is helping. Because without the grants that we get we cannot do it. In different stages of my career, ICRF was so helpful. … I got every sort of grant from ICRF until I got the professorship [grant]. … This is a seven-year grant and I cannot tell you how much peace it gives me to know that for seven years, I have funding that is promised to me. … It’s an amazing feeling.

What kind of improvements in treatment do you see coming up in the near future?

I think probably the combinatorial treatment of using epigenetics and another arm, probably immune checkpoint therapy, is really promising. I feel that there is big promise in this combination.

Are there any types of cancers in particular that you see this research helping?

Leukemia has been treated with epigenetics but now there are clinical trials for solid tumors, the big ones: the lung cancer, the ovarian cancer and there are good results there, so hopefully they will find different combinations for different cancers. What is very important to understand is the changes in methylation that I told you occur in almost all tumors. It’s different than what we know about genetic mutations. In one tumor you have mutation A, B, C and D. In another tumor it’s another combination. Here almost all tumors have changes in DNA methylation so it’s widely applicable.