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The ghost of Landsteiner


Stein and Moore and beginning work on gamma globulin
Gerald Edelman Scientist
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I was exposed to Stein and Moore who were the reigning protein chemists in those days, and who had invented the amino acid analyzer, and who thought I was quite daft for trying to do something like antibodies. The issue is very simply put: Sanger and Tuppy had done the first brilliant complete analysis of what's called a protein... insulin, which had a molecular weight of 6000, that's 6000 times the molecular weight of hydro... the atomic weight of hydrogen. They, Stein and Moore, who, by the way, got the Nobel Prize at the same time I did in chemistry. Stein and Moore had been working on the amino acid sequence of ribonuclease, the very important enzyme, and I think the molecular weight was of the order of about 13,700. Here I was, going to do the sequence of a molecule that had a molecular weight of 150,000. If that didn't put me away in the loony bin, I don't know what. But I in fact stayed at it and I remember quite clearly experiencing what I'll call an epiphany, although that's too dramatic a word.

The... what intrigued me at that time, as I said, was physical chemistry, so I took my antibody fractions out of that Cohn fraction II, and I started treating them chemically with a variety of tricks. One of the tricks was to break the so-called disulphide bond, the sulphur... sulphur bond that occurred in certain proteins from an amino acid called cysteine, to make something called cystine. And I was very proud of myself because I made a rotating amperometric electrode that would measure how many of these bonds I broke. At the same time I was very intrigued – and here we go back to my fake, my disastrous welding machine, or brazing machine of my youth – I was very intrigued with the ultracentrifuge. In those days they had this giant instrument called the analytical ultracentrifuge where you could measure the so-called sedimentation constant, how fast the molecule fell in a field of 300,000 times gravity – a very, very high-spinning rotor which contained a little optical system that you could look in... invented by The Svedberg, a Nobel laureate in Sweden.

And so I was working at my amperometric electrode one day when I said, ‘You know, maybe I should block these sulphydryls that I make when I cleave these bonds, and stick it in the centrifuge.’ I had been of course looking at the native molecule in the centrifuge and that made a nice peak. When I did this it broke those bonds and put it in the machine. It didn't seem to move at all compared to the native molecule, so I rapidly made some mathematical calculations about maybe it unfolded and that increased the... the drag and the solute, and maybe that accounts for why it's so slow; it doesn't sediment. It turned out that nothing... nothing of that kind could explain the result. The only thing that could explain the result was that I had cleaved the molecule and that the molecule consisted of chains. Well, we'll come back to that, but the main thing was that... I can't quite call that an epiphany. I'll tell you about others that like are contrasted with, but gradually it became clear to me that what I had concluded was contrary to what was in the literature and that was of course extremely upsetting but it does teach you something about science and the way it proceeds – mainly, that there's a lot of stuff in the literature that doesn't quite gel even though it looks that way. So that was the beginning of my total absorption and of course there were several thoughts that were associated with this.

US biologist Gerald Edelman (1929-2014) successfully constructed a precise model of an antibody, a protein used by the body to neutralise harmful bacteria or viruses and it was this work that won him the Nobel Prize in Physiology or Medicine in 1972 jointly with Rodney R Porter. He then turned his attention to neuroscience, focusing on neural Darwinism, an influential theory of brain function.

Listeners: Ralph J. Greenspan

Dr. Greenspan has worked on the genetic and neurobiological basis of behavior in fruit flies (Drosophila melanogaster) almost since the inception of the field, studying with one of its founders, Jeffery Hall, at Brandeis University in Massachusetts, where he received his Ph.D. in biology in 1979. He subsequently taught and conducted research at Princeton University and New York University where he ran the W.M. Keck Laboratory of Molecular Neurobiology, relocating to San Diego in 1997 to become a Senior Fellow in Experimental Neurobiology at The Neurosciences Institute. Dr. Greenspan’s research accomplishments include studies of physiological and behavioral consequences of mutations in a neurotransmitter system affecting one of the brain's principal chemical signals, studies making highly localized genetic alterations in the nervous system to alter behavior, molecular identification of genes causing naturally occurring variation in behavior, and the demonstration that the fly has sleep-like and attention-like behavior similar to that of mammals. Dr. Greenspan has been awarded fellowships from the Helen Hay Whitney Foundation, the Searle Scholars Program, the McKnight Foundation, the Sloan Foundation and the Klingenstein Foundation. In addition to authoring research papers in journals such as "Science", "Nature", "Cell", "Neuron", and "Current Biology", he is also author of an article on the subject of genes and behavior for "Scientific American" and several books, including "Genetic Neurobiology" with Jeffrey Hall and William Harris, "Flexibility and Constraint in Behavioral Systems" with C.P. Kyriacou, and "Fly Pushing: The Theory and Practice of Drosophila Genetics", which has become a standard work in all fruit fly laboratories.

Tags: William Howard Stein, Stanford Moore, Frederick Sanger, Hans Tuppy, Theodor Svedberg

Duration: 3 minutes, 49 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008