Now those were the three things: the size, the heterogeneity, and the... and the specificity, and that framework of challenge was the one that I lived in for a fair number of years, and fortunately was joined by colleagues of great talent, because otherwise we wouldn't have gotten anywhere. So the question of size had a potential solution in that splitting I talked about in the centrifuge – namely that when you broke the disulphide bonds you got smaller pieces. Well, I'd hoped, and it turned out to be the case, that one of the pieces would be small enough to do sequencing of the kind they did with ribonuclease.
The second problem was... was really interesting because it connected my medical experience and my chemical experience, and here I must say something about that. You really can't predict what the importance of... of a certain kind of experience might be until after the fact, so I hadn't realized how important it was to have had some medical exposure. And here I have to go off on another tangent but I think it's relevant to the question of heterogeneity. It's well-known amongst internists certainly that a certain disease called multiple myeloma, which was a disease of the cells that make antibodies – a cancerous disease – that they sometimes spill into the urine a protein called Bence Jones protein. Bence Jones protein had a peculiar property, and I should diverge once more to tell you the background of that, because it was against that background that I had perhaps the most complete break in trying to do the structure of antibodies.
It... Bence Jones protein was in fact the second protein ever discovered. The first was discovered by Liebig; it was albumin – that predominant protein in your serum – and they already knew in those days that when a patient was sick with certain diseases he would spill albumin, or she would spill albumin, into the urine, and the way you could tell it was you could heat the urine and you'd find that a black... a white cloud would appear – precipitated denatured albumin. And that wasn't a good thing. Well, it turns out that two Scottish physicians, Macintyre and Watson, were taking care of a man – a grocer, a wealthy grocer in Scotland – who had what they called mollities ossium, softening of the bones. It happened to be myeloma. And they heated the urine, à la Liebig, and what they found is that they got the precipitate but if they heated it a little more it went up clear again. So Watson actually wrote a letter to Henry Bence Jones who was a student of Liebig and was a practitioner in London, a fellow of the Royal Society of Medicine, and a rather well-known practitioner, and they said, ‘Here's what happened; what is it?’ And he hooked it up in his... cooked it up in his retorts and he concluded it was the deuterated hydroxide of albumin and that was good enough for the time. The main point was is what they called almost pathognomonic diagnosis – namely, if you cooked someone's urine and that had that phenomenon of going out of solution and then going back in, you had Bence Jones protein – that meant you had multiple myeloma – so you could really sort of show off and be brilliant without even talking to the patient. Well, I... I knew about this so I started to study myeloma and it turns out that in myeloma, a molecule that looked exactly like antibodies was present in the serum in huge amounts, and in fact sometimes in such large amounts that caused trouble in itself besides the cancer. So the thought occurred to me when I split the antibody molecule that maybe one of the pieces might be the Bence Jones protein. The second thought was: hey, but myeloma proteins are very pure. By the way, trivial pedantic detail: people tend to hyphenate Bence Jones, Bence dash Jones sort of English style. It isn't true – that was his middle name but the best of it is his uncle who is called Bence Bence Bishop of Beccles. Only in England.
