PHILADELPHIA REFLECTIONS
Musings of a Philadelphia Physician who has served the community for six decades

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Benjamin Franklin
A collection of Benjamin Franklin tidbits that relate Philadelphia's revolutionary prelate to his moving around the city, the colonies, and the world.

Science
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Nobel Prizes
Some Philadelphians won Nobel Prizes for work done here, or elsewhere. Some prize winners would deny they are Philadelphians, but their work was nevertheless done here.

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Right Angle Club 2012
This ends the ninetieth year for the club operating under the name of the Right Angle Club of Philadelphia. Before that, and for an unknown period, it was known as the Philadelphia Chapter of the Exchange Club. www.philadelphia-reflections.com/topic/175.htm

Academia (2)
continued.

Evo-Devo

{The Franklin Institute of Philadelphia}
The Franklin Institute of Philadelphia

THE oldest annual awards for scientific achievement, probably the oldest in the world, are the gold medals awarded by the Franklin Institute of Philadelphia for the past 188 years. Nobel Prizes are more famous because they give more money, but that in a way involves another Philadelphia neighborhood achievement, because Nobel's investment managers have run up their remarkable investment record while operating out of Wilmington, Delaware. In the past century one unspoken goal of the Franklin Institute has been to select winners who will later win a Nobel Prize, the actual outcome more than a hundred times. That likelihood is one of the attractions of winning the Philadelphia prize, but in recent years some Nobel awards have acquired the reputation of being politicized, particularly the Peace and Literature prizes. Insiders at the Franklin are positively fierce about avoiding that, so the Franklin Institute prizes have become known for recognizing talent, not merely fame.

{Dr. Sean Carroll}
Dr. Jan Gordon, Dr Sean Caroll, and Dr. Cliff Tabin

Within Philadelphia, the annual awards ceremony is one of the four top social events. The building will seat 800, but reservations are normally all sold out before invitations are even put in the mail. A major source of this recent success is clear; in the past twenty-five years the packed audience is a star in the crown of Dr. Janice Taylor Gordon. This year, she hurried back from a bird-watching trip in Cuba, just in time to busy herself in the ceremonies where she sponsored Dr. Sean Carroll of the Howard Hughes Foundation and the University of Wisconsin, for the Benjamin Franklin medal in the life sciences. Carroll's normal activities are split between awarding $80 million a year of Hughes money for improving pre-college education from offices in Bethesda, Maryland, and directing activities of the Department of Genetics in Madison, Wisconsin. His prize this year has relatively little to do with either job; it's for revolutionizing our way of thinking about evolution and its underlying question, of how genes control body development in the animal kingdom. Evolution and Development are academic terms, familiarly shortened to Evo-Devo.

{Dr. Carroll Butteries}
Dr. Carroll's Butterflies

My former medical school classmate Joshua Lederberg, also a resident of Philadelphia, was responsible for modern genetics, demonstrating linkages between the DNA of a cell, and the production of a particular body protein. For a time it looked as though we might confidently say, one gene, one protein, explains most of biochemistry. In the exuberance of the scientific community it even looked as though deciphering the genetic code of 25,000 human genes might explain all inherited diseases, and maybe most diseases had an inherited component if you took note of inherited weaknesses and disease susceptibilities. But that turned out to be pretty over optimistic. Lederberg got into an unfortunate scientific dispute with French scientists about bacterial mating, and now appears to have been wrong about it. But the most severe blow to the one gene, one protein explanation of disease came after the NIH spent a billion dollars on a crash program to map out the entire human genetic code. Unfortunately only a few rare diseases were explained that way, at most perhaps 2%. Furthermore, all the members of the animal kingdom turned out to have pretty much the same genes. Not just monkeys and apes, but sponges and worms were wildly different in outward appearance, but substantially carried the same genes. Even fossils seem to show this has been the case for fifty million years. Obviously animal genes have slowly been added and slowly deleted over the ages, but in the main the DNA (desoxy nucleic acid) complex has remained about the same during modest changes in evolution. Quite obviously, understanding the genome required some major additions to the theory's logic.

In late 1996, three scientists met in Philadelphia for a brain-storming session. Sean Carroll had demonstrated that mutations and perhaps evolution of the wing patterns of butterflies and insects took place during their embryonic development, and seemed to be controlled by the unexplored proteins between active genes. Perhaps, he conjectured, the same was true of the whole animal kingdom. Gathered in the Joseph Leidy laboratory of the University of Pennsylvania, the three scientists from different fields proposed writing a paper about the idea, suggesting how scientists might explore proving it in the difficult circumstances of nine-month human pregnancies, in dinosaurs, in deep-sea fish and many remote corners of the animal kingdom. Filling yellow legal pads with their notes, the paleontologist (fossil expert) Neal Shubin of the University of Pennsylvania, genetic biologist (Sean Carroll of Wisconsin), and Harvard geneticist Cliff Tabin worked out a scientific paper to describe what was known and what had to be learned. The central theme, suggested by Carroll, was that evolution probably takes place in the neighboring regulatory material which controls the stage of life early in the development of the fetus, and these regulatory proteins consist of otherwise inactive residual remnants of ancient animals from which the modern species had evolved. As the fetus unfolds from a fertilized egg into a little baby, its outward form resembles fish, reptiles, etc. And hence we get the little embryonic dance of ancient forms morphing into modern ones. In deference to the skeptics it would have to be admitted that the physical resemblance to adult forms of the ancient animals is a trifle vague.

{Haeckel's drawings of vertebrate embryos, from 1874}
Haeckel's drawings of vertebrate embryos, from 1874

Embryologists have long argued about Ernst Haeckel's incantation that "Ontology recapitulates phylogeny", which is a fancified way of saying approximately the same thing. Darwin's conclusion was more measured than Haeckel's and explanations of the phenomenon had been side-lined for almost two centuries. But it seems to be somewhat true that fossils which paleontologists have been discovering, going back to dinosaurs and beyond, do mimic the stages of embryonic development up to that particular level of evolution, and might even use the same genetic mechanism. The genetic mechanism might evolve, leaving a trail behind of how it got to its then-latest stage. Borrowing the "Cis" prefix ("neighboring") from chemistry, these genetic ghosts have become known as Cis-regulatory proteins as the evidence accumulates of their nature and composition. Growing from the original three scientists huddled in Shubin's Leidy Laboratories in 1996, academic laboratories by the many dozens soon branched out, dispatching paleontologists to collect fossils in the Arctic, post-doctoral trainees to collect weird little animals from the deserts of China, and the caves of Mexico, everywhere confirming Carroll's basic idea. Even certain forms of one-celled animals which occasionally form clumps of multi-celled animals have been examined and found to be responding to a protein produced by neighboring bacteria which induces them to clump -- quite possibly the way multi-cellular life began. Many forms of mutant fish were extracted from caves to study how and why they developed hereditary blindness; the patterns of markings on the wings of butterflies were puzzled over, and the markings on obscure humming birds. The kids in the laboratory are now having all the fun with foreign travel, while the original trio find themselves spending a lot of time approving travel vouchers. Many fossils of animals long extinct have been studied for their evolution from one shape to another, especially in their necks, wings and legs. Some pretty exciting new theories emerged, and are getting pretty well accepted in the scientific world. At times like this, it's lots of fun to be a scientist.

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