Philadelphia Reflections

The musings of a physician who has served the community for over six decades

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Philadelphia Chromosome
The Franklin Institute

Every Spring for the last 185 years, the Franklin Institute has honored the most distinguished scientists alive; Franklin would certainly be proud of the Institute named after him. In recent years, many awards were combined into two categories, the Bower Awards and the Benjamin Franklin gold medals. Unlike the Nobel Prize, the Franklin Institute Medals are not given for eminence in a designated field of science, but rather are given out by a hard working committee of scientists who ask themselves What are the really hottest scientific fields at present, and then ask panels of international referees Who is most eminent in that field? The awards thus effectively avoid fields that are temporarily stale and static, by being unrestricted in advance to particular fields. The approach of searching for the greatest minds rather than greatest achievement may well lead to the same award, but the method of choosing seems more harmonious with the spirit of Benjamin Franklin, who not only excelled in the field of electricity, but actually invented that whole field. The subtle shift in emphasis seems to have been well received; this year's Awards Banquet was over-subscribed before the invitations were printed, and a capacity audience of 800 attended a superb reception, dinner and audio-visualized live ceremony. Actually, the ceremony extends for a whole week, with scientific symposia and in-person meetings with high school students designed to interest them in science.

This year eleven scientists, the most prominent of whom were Bill Gates and Peter Nowell, received the medals. We'll get to Bill Gates in a while; for the present, let's concentrate on Peter Nowell, who invented the Philadelphia Chromosome. What's that?

{The Philadelphia Chromosome}
The Philadelphia Chromosome

Well, from 1921 to 1955, it was generally held that people, members of the human race, contained 48 chromosomes in every cell in their bodies. The chromosomes were thought to contain the genetic code governing our biological construction, explaining the difference between us and fruit flies, which for example only have four chromosomes per cell. After painstakingly examining the appearance of the chromosomes in different people and in cancer cells, it was then generally held that cancers never seemed to have any genetic abnormality. After all, the chromosomes of cancer cells looked exactly like those in normal tissue: Forty eight chromosomes, never differing in cancers, so go look somewhere else for the cause of cancer. Unfortunately, the state of scientific development fifty years ago can be summarized by noting that about that time it then became established we really only had 46 chromosomes, not 48. As for cancer, the M.D. pathologist Peter Nowell, then noticed in 1956 that a patient with chronic myelogenous leukemia had an extra translocation on one particular chromosome, giving it a funny shape. This translocation was furthermore present in every single other leukemic cell, suggesting that one cell had somehow undergone a single mutant change, and all the rest were its descendants. At least in CML (chronic myelogenous leukemia), it suddenly looked as though the cause had been found, since further study revealed the same was true of just about everyone who had CML. At first it was felt that while maybe the cause of this particular type of cancer had been found, every other cancer might still be caused by something else. Not so. From believing no cancers were genetic in origin, Peter Nowell started us on the path of now being confident all cancers have a genetic cause.

{Dr. Peter Nowell}
Dr. Peter Nowell

How could we all have been so wrong; can't scientists even count up to 46? No, as a matter of fact, in 1955 it was pretty hard. If we couldn't even tell how many of them were there, it's obvious the comment they all looked alike wasn't worth very much. As Peter shyly admits, his discovery was a result of being trained as a physician rather than as a life scientist; he knew what leukemia looked like, but at that time he didn't know very much about chromosomes. It happens chromosomes spend most of their lives expanded into tiny filaments too small to examine under the microscope. But as they enter the stage of cell division called metaphase, those filaments shorten and thicken up, becoming a lot easier to examine. As a pathologist, Peter didn't bother to stain his slides in dilute salt solution, but just washed them in tap water. The tap water had caused the cells to swell up and burst; those that happened to be in metaphase dumped their stubby chromosomes out where they could be stained and looked at. Simple. Doesn't everyone wash slides in tap water?

So fifty years ago, the general question of what causes cancer finally narrowed down to the right sort of specific question. Thousands of scientists, spending billions of dollars from the National Institutes of Health, sharpened the focus of their search considerably. It certainly looks as though someone is going to carry the search the final step, pretty soon. However, the fact that fifty years of intensive study still hasn't quite found the answer is an illustration of how fiendishly difficult the search really is. Each year that might have been spent futilely avoiding genetic searches would have added one year more before the answer was finally found. By the way, why is it called the Philadelphia Chromosome? In 1955 it had been decided by the scientific community that every genetic abnormality would be named after the city in which it was discovered. Dr. Peter C. Nowell of the University of Pennsylvania and the late Dr. David Hungerford of the Fox Chase Cancer Center were the joint discoverers, so obviously it was entirely a Philadelphia discovery; at that time it had been made a custom that genetic abnormalities were named after the city where they had been first found.

It would be a mistake to conclude that nothing new has been discovered in half a century of research. It has been established that not only Myelocytic Leukemia, but essentially every cancer starts with some genetic abnormality, which triggers the expression of "mini RNA". These abnormalities then apparently express a cancer-producing action by triggering an abnormal factor in the cell signalling system, called tyrosine kinase. Drugs with the effect of paralyzing that enzyme have been found to be curative in 95% of cases of chronic myelogenous leukemia, and some other forms of lymphoma. We're certainly getting closer, step by unexpected step, to the answer. In fact, we may be getting even closer to a point where drug research can jump to seeking cures without precisely defining how the cancer was caused. After all, if cancer is caused by a chain of cellular events, it may not matter where you break the chain. That realization appeared with, first aspirin and then the statin drugs, for treating heart attacks and strokes, even though we are still not completely clear about how atherosclerosis is produced. Meanwhile, the death rate from hardened arteries has dropped by half.

It wouldn't be right to omit mention of Peter Nowell's Quaker heritage. Although he isn't a Quaker, his mother was a Matlack, a direct descendant of Timothy Matlack, the Haddonfield Quaker who was the scribe for the first writing of the Declaration of Independence. Sitting in silent Quaker meeting, polishing and simplifying one's message before delivering it, is very good training for a habit of simple, direct thought. As Dr. Nowell phrases it, he is a chronic "lumper" of ideas, when so many scientists are content to be "splitters". Splitting complexity into its essential components is a useful approach. But somewhere, someone has to get to the heart of the matter.


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