February 7, 2011
The Matriarch of Modern Cancer Genetics
By CLAUDIA DREIFUS

Dr. Janet Davison Rowley, 85, is the matriarch of modern cancer genetics. Without her 1970s finding that broken and translocated chromosomes were a factor in blood cancers, we might not have the treatments for leukemia that are commonplace today. We spoke earlier this winter at her University of Chicago offices and also at the Hyde Park home she shares with her husband of 62 years, Donald Rowley, a research pathologist. An edited and condensed version of the interviews follows.

Q. You didn’t start out as a geneticist, but as a medical doctor. I take it your research career was accidental?

A. Absolutely. For much of the late 1950s, I worked a few days a week as a medical doctor at a Cook County Hospital clinic for retarded children. With young children at home, I would only work part time.

Then in 1961, my husband had a sabbatical from the University of Chicago to England. I needed something to do for the year we’d be over there. Because of my work with retarded children, I was interested in inherited diseases. It had recently been found that Down Syndrome was linked to an extra copy of chromosome 21. So, a friend arranged an introduction to Laszlo Lajtha, a hematologist in Oxford. He was doing groundbreaking work on the pattern of replication of bone marrow cells. Lajtha agreed to allow me to come to his lab to extend his work to replication of chromosomes, which I was interested in, and to learn more about his emerging field, cytogenetics.

Q. What was the state of genetics research in 1961?

A. The revolution was far from happening. This was less than a decade after Watson and Crick’s discovery. We were only beginning to have a notion of what DNA was like. There weren’t the right tools yet to stain it, cut it apart, examine and manipulate it.

Still, even with limited technology, there had been some advances. One of the most important came in 1960, when Peter Nowell and David Hungerford of Philadelphia discovered that one small chromosome was about half the normal size in many patients with CML, a type of leukemia. According to a convention at the time, this became known as the Philadelphia chromosome.

I enjoyed my laboratory work with Lajtha. I decided that when I returned to Chicago, I’d try to find another part-time job, though this time in research.

Q. How were you going to do that? You had few research credentials.

A. Well, I had a paper coming out in Nature with Lajtha on DNA replication in chromosomes. So at least I had that.

What I did was go to Leon Jacobson, the director of the Argonne Cancer Research Hospital, which was funded by a block grant from the Atomic Energy Commission; he had a pot of money. “I have a research project started in England that I’d like to continue with. Could I work here part time? All I need is a microscope and a darkroom. And by the way, will you pay me? I must earn enough for a baby sitter.” And he said yes to everything!

Once at the hospital, Dr. Jacobson, a hematologist, would sometimes ask me to look over the slides of his leukemia patients. Under the microscope, we’d see abnormal chromosomes — too many or too few in a group, though it would be hard to tell one chromosome from the other. The technology wasn’t there yet.

Q. Did this eventually lead to your important 1972 discovery of chromosome translocations?

A. It did. Though as luck would have it, I’d have to make another trip to England before that would happen.

In 1970, my husband took another sabbatical to Oxford. Just as we were leaving, this new technique of banding came out. With banding, genetic material is stained with special dyes before being examined under a fluorescent microscope. The bands on the chromosomes show up in contrast. You can see subtle differences, which you can use to identify the different chromosomes.

There was someone at Oxford who was really active with this technique. I was able to use his fluorescent microscope on nights and weekends to study things I was working on. By the end of the sabbatical, I knew it would be possible to learn more about those chromosomes we’d observed on the slides of Dr. Jacobson’s leukemia patients.

Q. And that’s how you discovered translocations?

A. Well, it was now possible to use the bands’ patterns to identify the different chromosomes.

Once I was in Chicago again, I looked at two different groups of similarly sized and shaped chromosomes from patients with AML-type leukemia. With them, chromosomes 8 and 21 were broken and had switched ends — the first known chromosomal translocation.

Later, I examined photographs of CML cells, one stained through banding and one not. You could see that chromosome 9 had an extra piece on it. This was the part of the Philadelphia chromosome that had broken off. Contrary to what had been thought, the Philadelphia chromosome didn’t represent a deletion of chromosomal material. The Philadelphia chromosome and chromosome 9 had each suffered breaks and swapped ends — the second translocation!

Q. And this was a revolutionary finding for genetics, right?

A. And cancer. More had to be known, of course. Why did this arrangement lead to leukemia? How consistent were these findings? In my lab, in 1977, we found a third specific translation in a rare type of leukemia, APL. So that showed what we’d observed with the other two wasn’t an anomaly. The third finding made me a believer. And by the late 1970s, there’d be common agreement: cancer is a genetic disease.

Q. It is sometimes said that the miracle drug Gleevec, which has proved so useful against CML and other cancers, could not have happened without your work. Is that true?

A. That’s very generous. But you had go through a lot of steps in between.

People accuse me of being too humble. But looking down a microscope at banded chromosomes is not rocket science. If I hadn’t found it, somebody else would.

Q. Do you think that the type of career you’ve had would be possible today?

A. No. I was doing observationally driven research. That’s the kiss of death if you’re looking for funding today. We’re so fixated now on hypothesis-driven research that if you do what I did, it would be called a “fishing expedition,” a bad thing.

O.K., we knew about the Philadelphia chromosome, and after banding we had the technology to discover gains and losses among the different chromosomes. But once you knew that, what were the implications of the gains and losses? That’s the “fishing,” because there wasn’t a hypothesis.

Well, if you don’t know anything, you can’t have a sensible hypothesis.

I keep saying that fishing is good. You’re fishing because you want to know what’s there.

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