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

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

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.

http://www.philadelphia-reflections.com/blog/1809.htm

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Lumpers In Constant Combat With Splitters

James Boswell's Book

Some colleges produce managers by teaching management theory, but in certain Ivy League colleges it is thought to be more useful to teach how to dominate a committee, eventually perhaps a board of directors, or a board of trustees. The handbook of instruction is James Boswell's Life of Johnson which is a rather large book of verbatim notes that Boswell took of his many lunches at a London club in the 18th Century. Boswell was a quiet mouse privileged to sit in the company of the great Dr. Samuel Johnson, surrounded by the most eminent intellects of the Enlightenment. Boswell carefully manages the background of each episode, describing the issue and the various arguments, and then -- Sam Johnson's booming voice settles the matter. After he speaks, the meeting is over.

Dr. Samuel Johnson

"Why, sir", says Johnson, and then look out for the one-liner to follow. We get the impression that Dr. Johnson used that "Sir" signal to indicate he had enough of these dumb arguments, and soon would come the growled epigram that scatters any token resistance. Boswell may have neglected to record instances where the great Johnson was defeated in debate, who knows. We are left with the distinct impression that if you engaged in lunch table conversation with Sam, you were almost certain to lose. So that's what Ivy League students are being taught: how to win a debate at a committee meeting, in the expectation they would spend much of their lives in committees, boards, and even cabinets. That's how the English-speaking world gets its work done and its decisions made. That's what lunches at the Franklin Inn Club, or the club tables of the Union League, are trying to do for the education of neophytes.

Chauncy Brewster Tinker

As the goggle-eyed student of the great Chauncey Tinker, who gave young Pottle his start in life, it was an awesome performance for me to watch. But the rules of this game never became entirely clear to me, I'm afraid, until the other evening when I listened to Peter Nowell describe in a half-dozen brief paragraphs how he had revolutionized prevailing theories of the cause of cancer. The Franklin Institute then followed the award ceremony by putting on an all-day symposium of notables who run elaborate enterprises in cancer research, essentially funded by the National Institutes of Health, your tax dollars at work again. Last year, the NIH dispensed thirty billion -- you heard me -- dollars in research grants to internationally known research entrepreneurs, and if you can stay awake during their talks, there must be something the matter with you. So far as I could see, they were painstakingly describing every grain of sand on the beach, whereas Peter Nowell made the whole beach electric and clear in ten minutes. Essentially, he was saying that each patient's cancer is caused by a long chain of events, starting with a single mutation within a single cell. All the other cancer cells of a patient are descendants of that first one, which triggered the cascade of chemical events now repeated by the descendants. To stop the process, you probably only have to find a way to break the chain at one vulnerable point. Then you have a cure, without necessarily understanding every other link in the chain.

Peter Nowell

Peter Nowell described himself as a "lumper", admitting that most scientists are "splitters". A splitter quite reasonably attacks a complex problem by isolating one small piece of it at a time; that's really a pretty good way to address overwhelming complexity when you encounter it. But you can be sure that people of that mindset should not be found in a President's cabinet, deciding how to save the world from impending disaster. Whether by their own genetic predisposition or as a result of peer pressure in their profession, they are habitual splitters. And it suddenly occurred to me why Sam Johnson's one-liners always won the argument; he was a lumper. Usually right, sometimes wrong, never in doubt. Witty as a Frenchman, but as quick as a rattlesnake. Cordial, perhaps, unless you disagreed with him.

We need more lumpers. If they get that way from the likes of Chauncey Tinker, we need to print more copies of The Life of Johnson. If they are born that way, maybe we need a breeding farm for lumpers, which is what the Assembly Ball amounts to. But don't get me wrong, we need more splitters, too. They just have to learn their place at the table.

http://www.philadelphia-reflections.com/blog/1810.htm

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Rara Avis

The Academy of Natural Sciences

School children grow up in Philadelphia with an image of the Academy of Natural Sciences as a place to visit dinosaurs. Indeed, it does have on display the first dinosaur skeleton ever to be discovered, as well as a number of others. However, only about a third of the building complex on Logan Circle is devoted to public museum displays. The rest is devoted to specimen storage, library and scientific work of the highest scientific eminence and value. In the scientific area, the most striking thing to a visitor is to notice how few windows there are. Scientists often spend their time looking through microsopes, so they don't care about windows. In a skyscraper business office that wouldn't be acceptable at all and the staff would all get the heeby jeebies and quit. In the business world, the number of windows your office has is important, especially if they are corner offices, the best kind.

Humming Birds

In one small area of the museum is a set of ingenious metal cabinetry containing 200,000 bird specimens, including every one of the 10,000 known species of birds on earth. In fact, about a quarter of all the "type" specimens are found there with red tags on their feet. A type specimen is the first known and described specimen of that particular bird, ever. That's a round-about way of relating that this is where Ornithology, the study of birds, began. It also tells you that when bird skins are treated with arsenic salts, they last a very long time; a considerable number of the specimens in the cabinets were contributed by Audubon, himself. New bird skins are acquired at the rate of a thousand a year, related to the scientific studies which go on, studying bird diseases, genetic changes due to environmental changes, and pollution effects. The recent uproar about Avian influenza revolves around the tendency for bird diseases to undergo genetic changes themselves, and become human diseases. A great many such bird diseases are maintained at the laboratory in case they are needed for a crash program of vaccine development. Environmentalists will be surprised to learn that the mercury content of bird feathers has actually declined in the past century.

Guinea fowl

With a good guide you quickly grasp the attraction of this topic of birds and birding. There are huge condors, with six-foot wingspreads; and one-inch hummingbirds. Birds of every shape and coloring, reaching some sort of extreme with the Bird of Paradise from New Guinea. Owls and eagles, ducks and chickadees. Hummingbirds defy the usual sort of nets; every single little hummingbird specimen was obtained by shooting it with a special little gun. If you see a hummingbird in your garden, just imagine what skill it takes to shoot one.

The ornithology department maintains an active program of loaning bird specimens to scientists all over the world, although this activity has recently been affected by computerization of the catalogue of specimens, resulting in a massive global internet conversation among ornithologists, sort of like a Facebook of a very special sort. For all this activity going on, the collection area is an eerily silent place.

And that's just birds, crammed into an organized space of, well, maybe fifty by two hundred feet, eight feet tall, fifty shelves per typical cabinet. Right next to it is the insect collection, perhaps taking twice the cabinet space. Insects are a lot smaller than birds, so each shelf has more specimens. That sounds like an awful lot of Latin names to try to remember. And a certain amount of danger, too. Several scientists died of arsenic poisoning before the full hazard was appreciated and contained.

http://www.philadelphia-reflections.com/blog/1816.htm

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