May 26, 2013 | by Wayne Lewis
As City of Hope celebrates its 100th anniversary, we offer a four-part interview with Art Riggs, Ph.D., chair of the Department of Diabetes and Metabolic Diseases Research. Many of City of Hope’s best-known breakthroughs came through his lab. In this series, he casts an eye back to some of his greatest scientific contributions — and forward to the advances on the horizon.
In Part 1, Riggs talks about his research revealing methylation to be a key mechanism behind epigenetic changes. Largely ignored at the time of publication, the paper reporting his findings is now a milestone in an active field of study that encompasses research into how cancer develops and how we can defeat it.
When you first came to City of Hope in 1969, one of the things that really drew you was that geneticist Susumu Ohno, D.V.M., Ph.D., was already on faculty here. He had produced a paper about X-chromosome inactivation. What was Susumu Ohno’s influence on you as a young scientist?
I was fascinated by what Dr. Ohno had discovered. He had discovered that every cell in a female mammal, including humans, have one of the X chromosomes completely shut off. All of the genes on the entire X chromosome — and there are 1,000 or so — every one of them is turned off. Ohno and [English researcher] Mary Lyon were the co-discoverers of that phenomenon.
At that time, it seemed impossible. There was no way for us to explain how that could possibly be done. It was an intellectual puzzle.
That’s how I got started thinking about what we now call epigenetics.
|Art Riggs on perseverance:|
|“Any idea that is transformational will be initially rejected. And any idea that’s accepted immediately is probably not that good, in that everybody would have had that idea. The ones that are rejected are potentially the most important.”|
At that time nobody used the word “epigenetics” to describe things like the X-chromosome inactivation. [English scientist Conrad Hal] Waddington had coined the word something like 20 years earlier, but it had fallen into disuse. It’s been rediscovered and now we would call what Ohno discovered the first mammalian, very clear epigenetic phenomenon — where you have this very stable inheritance from the progenitor cells to the daughter cells, that they remember their past identity.
I got hooked on X-chromosome inactivation before I came to City of Hope. Ohno was here, so I was interested in coming here. I came to City of Hope to establish my own independent laboratory. I came in at the associate professor level.
Quite frankly, I didn’t have any useful ideas immediately. Around 1975, I had sort of a “light bulb moment.” I said, “Oh, if we use the properties of these DNA methylation enzymes, then we can explain many aspects of X-chromosome inactivation.”
Susumu Ohno, when he heard about that idea, says, “Yeah. That’s important. You should try to publish that.”
Another person who was also very influential was [hematologist] Ernie Beutler. Ernie Beutler was at City of Hope in the ‘70s, and he was also interested in X-chromosome inactivation. He encouraged me to publish and get that idea out there as well.
It was probably a good thing that they did encourage me, because then as now — things haven’t changed that much — new ideas are usually rejected. Sure enough, the first time I tried to publish it, it came right back rejected.
I finally got it published in a rather obscure journal, and fortunately, a few scientists noticed it. The idea influenced their research and the data started coming in to support the idea.
And then things kind of snowballed. By the ‘80s it was accepted as being a large part of the explanation of the epigenetic stability of the X-chromosome.
And certainly that 1975 paper is somewhat of a landmark now. It’s highly cited. And it goes a long way to explain some of what happens in the development of cancer.
Epigenetics is now part of our standard terminology. I think this last year, in 2012, there were something like 4,000 papers that talked about various aspects of epigenetics. Probably more than 1,000 of those are talking about DNA methylation. It’s a very large field.
It’s fascinating to think that there’s a root there in an underappreciated paper from an obscure journal. Being the author of that underappreciated paper from an obscure journal, what’s your vista like at this point?
I was told by my mentor at the Salk Institute, “Art, most people think it’s important the number of people who pay attention to your work in the first year or two after it’s published.” He says, “That’s nonsense. The only citations that are important are the ones that you get 20 years later.”
And he’s right, of course. The ones you get 20 years later, they show that you’ve really done something.