top TOP
January 31, 2023

Howard Cedar, MD, PhD

Hebrew University-Hadassah Medical School

ICRF Research Professorship Grant Recipient

Research on DNA Methylation Leads to Blood Test to Detect Cancer

ICRF spoke to Howard Cedar, MD, PhD, and Yuval Dor, PhD, of the Hebrew University Medical School, about their pioneering work in DNA methylation, a molecular process that turns genes on and off, and the recent development of a blood test for the early detection of cancer, which is based on this research. Professor Cedar is the recipient of numerous awards for his pioneering discoveries, including the Israel Prize in Biology and the Wolf Prize in Medicine. He has the distinction of being ICRF’s first Research Professorship Grant recipient, the most prestigious ICRF grant category, and has been supported continuously by ICRF since 1987. 

Professor Dor, a previously funded ICRF grantee, spent many years working in Professor Cedar’s lab. He applied the findings in DNA methylation, and developed a breakthrough blood test for the early detection of cancer. The test examines DNA in blood and is capable of detecting more than 30 different kinds of cancer, even before there are clinical symptoms.

Read the full transcript below:

Chaim (Howard) Cedar: Hi, my name is Chaim Cedar. I’m a professor emeritus at the Hebrew University in Jerusalem in the medical school, and I’d like to tell you a little bit about our research over the unbelievable time of about 40 or 45 years.

So, our research is interested in, or concentrates on, something called epigenetics. And the principle is very simple. All of us are built from parts, like a big Lego item, and we have many, many, many, many parts in our body. The information for making those parts comes from our genes. The genes are written into DNA in the chromosomes, and this gives information to the cells—it serves like a book or an encyclopedia—for the cells.  It tells them how they should build the different proteins—the different pieces of Lego—to put together the entire body.

What we discovered about 40 years ago is that, in addition to that basic textual language, there’s another language attached to our genetic material. It’s an annotation. This annotation is just like you would annotate a text in English or Hebrew. The cells are able to annotate the book of DNA—the book of genetic information. And this annotation, of course, is not with a pencil or a pen; it’s done chemically. It’s done chemically through the use of a very simple molecule called methyl— methyl group. And what this meant was that what these methyl groups do is tell the cell how to use the genetic material.

Okay, I’ll give you a quick example. We have information in our body for making eye color. So, some people have brown eyes and some people have blue eyes. Somebody who has blue eyes, for instance, only his eyes are blue. That means that that gene, that piece of information—that color— is not being used in all the different places of the body; only in the eye and that is done by methylation. The methyl groups say that all over the body, the information for eye color is methylated. It has methyl groups and only in the eye, [outside of the eye] it’s unmethylated it doesn’t have a methyl group, and this gives the body information on where the different pieces of Lego the different components of the body should be expressed.

This is a very important piece of information because this information is what allows the body in the first place to develop into an organism, to make different tissues. This information is also important for diseases. For instance, one of the major things that happens in cancer is not so much that the information is different in the cells but, rather that the annotations are different and the cancer cells are doing completely the wrong thing with the information they have. So, this additional layer of information, this annotation called DNA methylation, is a very important part of the development of diseases. It provides a mechanism for us to adapt to our environment. It probably plays a role in aging. It’s a very, very important aspect of the language of genetics, or as we call it, epigenetics.

And it turns out that with lots of ingenuity, originality, and creativity, you can do many things once you have this information, and that’s where my good friend and colleague, Yuval, comes into the picture.

“The goal of medicine is to try to prevent these diseases [cancer]. This is the place where basic research comes to the fore, and again, I give all the credit to the ICRF.”

Professor Howard Cedar

Yuval Dor:

Yeah, thanks. Hi. So, my name is Yuval Dor. I’m also a professor of biology at the same medical school as Chaim, one floor above Chaim. I joined, I guess, 30 years later, and I’m interested in a topic called tissue dynamics—understanding where and when cells in the body are born and when they die. It turned out that the method discovered by Chaim — that you just described.

This method of unique annotation of each cell type in the body has a very surprising application that relates to our ability to detect diseases. The fundamental phenomenon that we’re studying here is the fact that when cells die in the body, they release small fragments of their DNA to the circulation, and those fragments travel through the blood for a short time. It turns out that if you are able to identify those specific annotations — those methylation marks — on those fragments of circulating DNA, you can essentially trace the tissue origins of those fragments. So, if you can identify a piece of DNA that circulates in your blood, the annotation, the methylation mark, that says this must be coming from a breast cell, actually tells you that there was a breast cell that has recently died in the body of that individual.

It turns out that this can be done in a very specific and very sensitive manner and is reflective often of pathologies. Elevated levels of breast-derived so-called cell-free DNA in the circulation, for example, have a very good correlation with the development of breast cancer, and higher levels of pancreatic DNA circulating in the blood, by the same principle, are indicative of the early stages of pancreatic cancer. Many, many pathologies are reflected in elevated levels of cell-free DNA in the circulation that can be identified using that principle of cell type-specific marks or epigenetic marks, and this, we think, is going to be the basis for how we’re going to diagnose many diseases, in particular cancer, in the coming years.

This is a very exciting direction and a very exciting field in diagnostic medicine. Right now we’re focused on, you know, the basic principles of that technology, but there are also, you know, other entities, including startup companies, that are starting to really apply that to real life. This is really an exciting journey that, I think, takes us from really fundamental discoveries made by Chaim over the last several decades on how this is the organizing principle of life to this surprising application that can be used for an important task such as the early detection of disease. This goes even beyond cancer to early detection of Alzheimer’s disease and additional conditions, so this is really very exciting.

Cedar: Yuval, are there any indications that this type of blood test actually can detect cancers early on even before they’re diagnosed?

Dor: Even before they are diagnosed right now. So, yes. It turns out that only for a few cancers we have right now, biomarkers for early detection, like mammography in breast cancer or PSA for prostate cancer or colonoscopies. In many cancers there’s no there are no biomarkers in the early earliest indication of diseases typically at the late stage, for example, in pancreatic cancer and there’s already pretty strong evidence that at an early, that is operable, stages of cancers in many cases there is already information released to the blood that can be detected by identifying those accurate indications of cell identity or the cell of origin. There are very exciting demonstrations that this can actually work. So, the hope is to kind of de-stage, that’s the professional term, to identify cancers at an earlier stage. That is still when the tumor is still localized and can be removed.

Cedar: So, this is going to save a lot of lives, it seems to me.

Dor: This is the hope of many, many people right now, and really, it came as a surprise to many that the method of choice for identifying the tissue origins of self with DNA and therefore diagnosing cancer turns out to be detecting those methylation patterns on those annotations that you have discovered, so this is really exciting and satisfying.

Cedar: Wow! What wonderful, wonderful work and as you say very exciting.

Dor: It is exciting!

Cedar: I’d like to add something here that I think is very important that has to do with the ICRF. When I started my work a very long time ago here in Israel, I had decided that I wanted to work on basic biology. For those of you who don’t know what that means, it means that I was just plain curious to know how biology works, and there was nothing on my mind about curing diseases, making an agricultural breakthrough, getting rid of viruses, or anything like that. Nothing about making people more healthy. It was not my intention. My intention was to learn pure basic science about how biology works. And along came the ICRF, which was devoted to treating and solving the problem of cancer, and they saw my work, and they said—and this is not a simple thing—they said we understand that if Chaim Cedar will uncover the secrets, the basic secrets, of how cells work, that can be applied to understanding cancer. And they supported me for many, many, many years.

I must say, any normal fund would be disappointed because they didn’t cure any cancer. I didn’t treat any cancers, and I didn’t really detect any other diseases. And it turned out in the end that the ICRF had the right approach. They understood biology much better than many, many other funding organizations, and they realized that the way to handle the problem of cancer is to first understand it, and I give them a lot, a lot of credit.

And I just want to add one more thing to that, which I think is important, and that is that we very commonly think about treatment. A lot of money goes into treating tumors that already are present and to stopping them from spreading or trying to kill them or trying to slow them down. Where the goal of medicine is not really that. The goal of medicine is to try to prevent these diseases. This is the place where basic research comes to the fore, and again, I give all the credit to the ICRF.

Dor: I joined Chaim, and I’m also a happy recipient of an ICRF grant development award for pancreatic cancer. The Barbara Goodman Career Development Aware for Pancreatic Cancer back in 2005 was very important support. I think it was one of the first grants that I ever got. So, I’m also grateful, but I think that the approach of supporting basic research is the most important thing towards translational research. It’s important and unique and proves itself.

Cedar: Thanks for your attention.

Dor: Thank you.

Help End the Suffering Caused By Cancer

The answer to cancer is research. Support groundbreaking cancer research in Israel today: