Tuesday, September 28, 2010

Philadelphia story

Posted by Nathaniel Comfort on 09/28 at 07:12 AM

Fifty years ago, Peter Nowell, a physician at the University of Pennsylvania, and David Hungerford, a postdoc working at Fox Chase Cancer Center on the outskirts of Philly, discovered the first cytological correlate of a human cancer. Today, Sept. 28, Fox Chase is honoring the discovery with a symposium, to be held at the Chemical Heritage Foundation.

The so-called Philadelphia chromosome is a version of our smallest chromosome—#22—that has a piece missing. Nowell and Hungerford found it in 1960, in the blood of patients at Philadelphia General Hospital who had chronic myelogenous leukemia. In the 1970s, Janet Rowley found that it is a translocation—an exchange of chromosome segments—between chromosomes 9 and 22. Despite fifty years of cytogenetics, the technology did not exist in 1960 to make such a fine distinction.

Nineteen fifty-nine/nineteen sixty was the heart of the human chromosome gold rush. In 1956, Joe Hin Tjio and Albert Levan discovered that human cells have only 46 chromosomes, not 48 as had been believed since the 1920s. Human geneticists around the world began to find anomalies in chromosome number and to correlate them with human disease.  A group under William Court Brown at Harwell in Edinburgh correlated several conditions of anomalous sexual development with variations in the number of sex chromosomes. Jerome Lejeune in Paris correlated Down Syndrome with a trisomy of one of the smallest chromosomes—now identified as #21. John Edwards, at Oxford and Klaus Patau, at the University of Wisconsin, found other trisomies.

Nowell and Hungerford didn’t find the presence or absence of a chromosome—they found a different chromosome. “We were looking at different kinds of leukemia,” Nowell told me, and trying to find a chromosomal correlation. In Philadelphia, the staff at nearby Presbyterian Hospital would draw blood, or allow Nowell to draw blood, from leukemic patients so that he and Hungerford could look at their chromosomes. In the acute leukemias, they found no consistent chromosome abnormality. In one of the chronic leukemias, however—chronic myelogenous leukemia, or CML—they found “this little abnormal chromosome that was present in every cell of every case.”

“What we couldn’t tell,” Nowell said, “was whether it was a deletion or a translocation, because the piece that was missing was so small that you couldn’t, in those days, without banding, tell whether the missing piece was stuck on some other chromosome.” Drosophila geneticists had long been able to stain chromosomes such that characteristic patterns of light and dark stripes appeared, which acted like signatures for the various parts of the chromosomes. All the human geneticists had to go on in the sixties was overall shape and size. Another type of rearrangement, called an inversion—in which a chromosome segment breaks off and reattaches upside-down—had been described in Drosophila in 1917.  “It wasn’t until the seventies,” Nowell said, “when banding techniques came along and specific cytogenetic changes in other leukemias, associated with other leukemia types, were identified, that people came to really realize that this was a way of identifying a particular genetic change that was clearly central to the causation of the tumor.”

The Philadelphia chromosome was a landmark: the first cancer associated with a specific chromosomal change. But technically, it showed how primitive human cytogenetics still was. Banding was introduced in 1968—Janet Rowley used it to demonstrate the Philadelphia translocation. By the end of the sixties, cytologically speaking, humans had just about caught up to where Drosophila had been back in the teens.

Check it:
A. G. Baikie et al., “Chromosome studies in human leukaemia,” Lancet 274, no. 7100 (1959):425-8

A. G. Baikie et al., “A possible specific chromosome abnormality in human chronic myeloid leukaemia,” Nature 188(1960):1165-6

J. H. Edwards et al., “A new trisomic syndrome,” Lancet 1(1960):787-90

Jacobs, P. A., A. G. Baikie, W. M. Brown, T. N. Macgregor, N. Maclean, and D. G. Harnden. “Evidence for the Existence of the Human “Super Female"." Lancet 274, no. 7100 (1959): 423-5.

Jacobs, Patricia A., and J. A. Strong. “A Case of Human Intersexuality Having a Possible XXY Sex-Determining Mechanism.” Nature 183 (1959): 302-03.

J. Lejeune, M. Gautier, and R. Turpin, “The Chromosomes of Man,” Lancet 1, no. Apr. 25 (1959):885

Nowell, P. C., and D. A. Hungerford. “Minute Chromosome in Human Chronic Granulocytic Leukemia.” Science 132, no. 3438 (1960): 1497-97.

K. Patau et al., “Multiple congenital anomaly caused by an extra autosome,” Lancet 275, no. 7128 (1960):790-93.

J. D. Rowley, “Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia,” Ann Genet 16, no. 2 (1973):109-12.

A. H. Sturtevant, “Genetic Factors Affecting the Strength of Linkage in Drosophila,” Proc Natl Acad Sci U S A 3, no. 9 (1917):555-8.

Tjio, Joe H., and Albert Levan. “The Chromosome Number of Man.” Hereditas 42 (1956): 1-6.

Tags: cancer, david hungerford, human genetics, peter nowell, philadelphia chromosome