What we’re doing here is unpacking a box of material that dates back to the undergraduate days of Oliver Smithies, and the first thing that we’re looking at is a box of film, which is probably not worth looking too much at, but it’s dated November-December ‘58. These are films taken actually probably during the research period, not the period that the book is concerned with. I think we’ll forget about that. I think it’s not really terribly worthwhile worrying about.
We’re going to unpack the box layer by layer. The first package that we come across is a collection of cards which are notations from quarterly reviews. A sort of abstracting system that was used by investigators who were trying to search the literature.
The first one is G.S Hartly as it says, not very important. We’ll turn them over, I’m having difficulty holding this. Nothing notable in this. Here’s another abstract from Comptes rendus Carlsberg, and various interactions, just a notation of something that was looked at. Nothing very notable. Here again some references, they’re really rather unintelligible at this point, though. Here is something on Donnan equilibrium which was important in my thesis problem, so it’s probably dating back to thesis time. That’s even by Donnan himself. Various notations of articles read primarily in relation to the work I was doing for my thesis, so that bunch of cards dates back to the time when I was doing research for my thesis.
The next one we come across is notes a lecture by A.G. Ogston, Sandy Ogston, who was my thesis advisor and undergraduate advisor. This goes back probably to the time when I was an undergraduate and is notes on a lecture given by him on pH and making sure that one understood what pH really meant. It’s quite a nice summary of what was being taught at that time and still completely relevant even today. That’s the pH A.G. Ogston document.
The next document is lecture notes from a course given by Bowen, and I don’t even remember what his other name was, on the absorption of light and atomic structure, so it gives some idea of what was being taught at that time about light and the interaction with molecules. Flicking through a few pages it talks about the state of electrons under different circumstances and the absorption of light. Quite a nice series of notes and completely understandable at the time, though I must say I would have trouble understanding it now. But the notes are quite good notes and go on for probably 20 pages.
The next one we come to is clearly notes from lectures that were given again by Ogston. This was during the time that I was still an undergraduate working towards my honors bachelor’s degree in animal physiology and Sandy Ogston came back at that time and taught various things that nowadays we would think of related to molecular biology. And here he was talking about some physical principles in biochemistry. A title which really is very much at the heart of how he thought and what he taught about, that you had to understand the physical chemical aspects of the chemistry of the body. So he’s talking about thermodynamics can define the possibilities of a reaction taking place since it’s concerned with the distribution of energy in systems. In other words, he was saying you can’t make something happen unless you provide energy for it to happen, and talked about the ways that energy is described. There’s actually free energy and he talks about the conservation of energy and the entropy of a system, which at that time was still rather a difficult concept for me but later became clearer. Nowadays we think about entropy being the order of the system, or the disorder rather of a system, so all systems tend to go from an ordered state to a disordered state if they can change. So, entropy increases as disorder increases, and this is him lecturing about that. I’ll turn over the pages.
He talks about osmotic pressure, which was later the topic of my thesis, so he’s deriving the equations for osmotic pressure. Several pages of this. He’s considering, for example, on one page he’s considering a situation where there is a mixture of a solution of sugar, sucrose, in water and in equilibrium with water itself with a boundary between them, a membrane between them, which is impermeable to sucrose. So it’s not an easy concept at first, but in the end quite easy, that if you have water mixed with sucrose, the concentration of the water is lower than the concentration of water when it’s in pure water. So water is at a lower concentration, and if water can pass through the membrane it will pass from the higher concentration into the lower concentration in the sucrose water mixture. And that will happen and can be opposed by applying a pressure and that pressure to prevent the dilution of the sucrose solution by water is the osmotic pressure. And that became my thesis problem. He talks about that being relevant to the lymphatic system and various other things of that type. The lecture is… my notes of the lecture are quite extensive so it was obviously important to me.
Energy of cellular metabolism, he’s talking about later, became part of the first scientific article on which I was an author. Notice I don’t say “which I wrote.” I was an author on the paper but Sandy wrote the paper out of some discussion that arose during our meetings.
We’re going to bind this set of notes into a little binding. Many pages of it. This must have been a series of lectures, yes, because here it starts again on page 1, now it’s talking about the equilibrium constant and free energy, free energy being the work that you can get from a particular system. We’ll rebind these, I’m going to stop the recording now.
The next set of notes is from Hinshelwood, he was a professor of physical chemistry and had a lot to do with teaching principles of reaction rates and so on. I think I’m not mistaken, maybe he got the Nobel Prize, I’m not certain. But notes on chemical equilibrium, thermodynamical approach. I was very interested in thermodynamics.
The next package is Hinshelwood lecturing on the rate of chemical changes. It’s rather interesting to me because the first lecture I ever gave in relation to chemistry was given in University of Toronto, I think, in a course taught by Charles Hanes, professor C.S. Hanes, and I remember this lecture very well giving it because there was the sun shining through the window and I could see my shadow on the wall, and I remember being so nervous that I could watch this shadow talking while I was giving the lecture. It was a pretty out of body experience, but I was actually lecturing on material that is covered by this set of lecture notes on the rate of chemical change by Hinshelwood.
The next pages actually a final examination for my undergraduate honors degree in animal physiology and it’s a copy of the final examination – oh no, it’s the chemistry one. I took the chemistry one after physiology so that… Let me back track. I did an honors degree in animal physiology which I got first class honors, then I joined the second and third year of the chemistry degree, bachelor’s degree, and this is one of the final examination papers. I’m curious to see what it says. The date is 22 of June 1948, a day before my 24th birthday. The exam was a practical exam, as you can see if you read it, you’re provided with material and expected to investigate the parameters of hydrolysis of (???), and you also had to investigate and identify substance C, and that’s an interesting element. I don’t remember what substance C was. Although I don’t remember what C was, I remember one examination prompted by my undergraduate friends, Jeffrey Thomas and Tubby Bernstein, who were undergraduates in Balliol a year more senior than me, and had worked out the best way to do organic chemistry in the medical school was not to follow the usual recipe but was to identify all substances by three simple tests: taste, smell, and appearance. And I had one final exam chemical I had to identify, which was rather oily looking, rather like glycerol, but it smelt of caramel and tasted acidic, and I thought that with a caramel smell it must have something to do with carbohydrates. And what’s a common glycerol like substance that comes from sugars, and I thought it might be lactic acid, and I did the confirmatory test for lactic acid and I was out of the exam in ten minutes.
The next package is notes on lectures by Bell, Ronnie Bell, R.P. Bell. He was the chemistry tutor in Balliol College and was a very rigorous chemist. I don’t know what he’s lecturing on at this point here, lecturing on the energy of solutions, a long series of lectures going on for many pages. I remember having one of my early tutorials with Ronnie Bell. He’d asked me to write an essay on the Pauli Exclusion principle and the period table, and I had had a grand time writing my weekly essay on this topic, which an absolutely fascinating topic in its first right, and I got half way down the first page of my essay and Ronnie found that I didn’t understand what I’d written and I couldn’t justify the statements that I’d written, so we never got beyond the first page where he made it very clear that you never write down anything you can’t justify and anything that you don’t understand.
The next one we come across is physiology, oxygen, and carbon dioxide transfer (?), and it’s labeled O. Smithies, so I think it must have been one of my weekly essays. I don’t quite know what it is but we’ll read it and see. And the notes that I’ve written, when I review them, were really quite good.
The next one is continuing notes on Ronnie Bell’s lecture on the kinetics of solution reactions. They’re quite extensive, many pages, so it must have been several lectures.
The following package contains notes on a series of articles that I read in relation to the importance of phosphate compounds and energy metabolism. It is a very important package for me because it includes one paper that I remember perhaps better than any other paper that I ever read, being equivalent to opening a new book in one’s life. Perhaps as I go through them, this will become more obvious. The first article is by McFarland, published in 1939 on the Phosphorylation of Carbohydrates in Living Cells. And a second paper, also by McFarland, on Changes in Phosphorid Distributions During Anaerobic Glycolis in Brain Slices. Another paper is talking about the inhibition of glycolysis by Gamill, 1939. Carbohydrate Metabolism in the Embryo by Needham, 1937. One on the Function of Phosphate in Cellular Simulations, 1942, by Kalckar, talking about the coupling of phosphorylation with fermentation and respiration. A preface to understanding why phosphate is involved in the metabolism of carbohydrates, and indeed of all biological substances. This collection of articles and my notes on them has one article which I consider, as I mentioned, to be the most important article that I ever read in terms of enjoyment. It is an article by Fritz Lipmann in Advances of Entymology, 1942, volume 1, page 99, “Metabolic Generation and Utilization of Phosphate Bond Energy.” In this article, Lipmann introduces to me the concept of energy rich phosphate and importance of energy rich phosphate in metabolism and changing energy, low energy phosphate compounds. For example, phosphate S turns (?) into high energy compound, phosphate and hydrides. ATP is a phosphate and hydride, two phosphate and hydride groups, and one phosphorester group, so it has two high energy phosphates, and one low energy phosphate. And his book, this article by Lipmann is so deep in my mind that I remember what the book looked like, where I was when I read the book, and the feeling that … I even remember what the type was like. It was one of those revelations that occur in a young scientist’s life.
The bunch of papers, starting with The Yellow Enzymes, chapter 13, Sumner and Summers, and enzymes. Just a review of reading some papers.
This package contains what is almost certainly an essay written for the weekly meeting with my tutor. I don’t know, it almost certainly was Sandy Ogston, during my physiology training. It talks about cellular oxidation and its application to carbohydrate metabolism. It is primarily a discussion of Kreb’s cycle, or one of Kreb’s early cycles, maybe, not the final one. It’s sort of interesting to read, but obviously dated.
The next package is a complete change in topic. Now obviously it’s under the direction probably of Professor Whitteridge, David Whitteridge, a neurobiologist, and these are notes on various papers related to the central nervous system. A fairly substantial package of notes from the literature. The following package contains what are almost certainly two of the weekly essays that one would write for one’s tutor in response to some topic assigned the week before. So, one of them is answering the questions “how far have studies of behavior contributed to the study of the physiology of the cortex?” and that is the question that I was asked to answer. The essay that follows is what I wrote in response to it. It beings with “the study of behavior is a science which would appear at first sight to be ideal for investigation of the physiology of the cortex” etc., and the second essay is on the bearing of studies of behavior on problems of localization of function in the central nervous system. And, again, a weekly essay.
This package contains notes on a few papers related to the sensation of pain and detection of painful stimuli. I remember having to write a weekly essay on the topic. One of the items which came up, I don’t know whether I can find the references for it, was a description of an animal in early phases of evolution, which the investigator described as, or called, a protopathic (?) animal. An animal which had a very primitive ability to detect basically anything other than pain, versus later evolutionary stages where the animals had evolved to the stage where they were so called epicritic animals, where they could distinguish things such as color, sound, various much more sophisticated things. One author wrote a criticism of this idea that there was a protopathic animal, and I remember quite a lot of what he said, because it was in one complete sentence, which I can’t reproduce completely, but it started off like this (he’s referring to the protopathic animal) “such an animal, if it could propagate its bewildered kind, which appears doubtful, could respond to…which in response to a stimulus which it could not understand, from a stimulating agent, whose nature it had no means of determining, could only respond by curling and mixturating (???).” I remember learning that by heart because it was one sentence, and incredibly structured sentence describing his opinion of the protopathic animal. I’ll try it again. “Such an animal, if it could propagate it’s bewildered kind, which appears doubtful, could have little survival value, for in response to a stimulus which it could not understand from a stimulating agent whose nature it had no means of determining, could only respond by curling up and mixturating.” I almost got it right.
A change in topic here. Some notes on blood coagulation and then an essay for a weekly essay, I assume again, on the possible structure of hemoglobin. These are identified because they’ll have some title and my name, O. Smithies, will be on the right hand side. So this has physiology on the left, O. Smithies on the right, number 1 and “The Possible Structure of Hemoglobin” is the title of the essay. The next several packages are weekly tutorial essays in the nervous system time of my career, when David Whitteridge was my tutor.
There are a few notes that are, that I remember rather well regarding the electrical conductivity of nerve fibers, particularly work by Katz and people. And I have some notes on this that begin with electric excitation of nerves by B. Katzen, 1939, brief notes. And I remember being quite fascinated by nerve conduction and beginning to think that I might like to do my research in things related to the nervous system. This was before Sandy Ogston came back and began to talk about molecular biology things. It was back in the time when I was a student of David Whitteridge, as I’ve mentioned before. So several articles in relation to nerve conduction.
The next one is an essay, again, a weekly tutorial essay on the adrenal cortex and various references that I had read in the preceding days in order to write this essay.
A summary of David Whitteridge, one rather short summary, of some things that Whitteridge was teaching me when he was my tutor and he was lecturing. This essay was on glycolysis and its beginning my understanding of what happened in phosphorylation and oxidative phosphorylation of biological compounds during the generation of ATP, which is part of the problem that I raised with Sandy Ogston in an essay that I haven’t yet found, that leads to my first paper. When I say “my first paper”, it’s Sandy Ogston’s paper, and I’m listed as a co-author, as a scholar of Balliol College, Oxford, published in 1948 in Physiological Reviews. So a fun article because sometime later, maybe thirty years later, in other words, 1978 or thereabouts, somebody came up to me and said “are you the Dr. Smithies who had an article in Physiological Reviews?” and I said yes I am, and the person said “oh I thought you were dead!”
This is an essay on pain and the nature of painful over actions, hyperalgesia, and hyperesthesia, written presumably for David Whitteridge. This is probably close to the essay when I had that remembrance of the article about the protopathic and epicritic animal. I’m hoping to find that reference but I don’t know whether I’ll be able to.
I have here one essay on “what if any has been the use of comparative studies on the physiology of the cerebellum?” I don’t remember writing this, of course, but I do remember that I always thought that cerebellum was an extremely interesting organ, and one that could be studied systematically, because it was so repetitive, and so important for the control of muscular movement as seen in the delicacy of movement of a cat, which has a huge cerebellum and a rather small cortex. So it’s very graceful but rather stupid. Whereas humans have a rather big cortex and rather small cerebellum, and so they’re not very graceful, at least most of them.
I found a short reference to the use of x-ray diffraction methods, physical considerations regarding the application of polarizations, optical and x-ray diffraction methods. It’s rather interesting to me because x-ray diffraction was hardly – was in its infancy when I was a graduate student. When I went in thinking about where to go for a post-doctoral fellowship, I visited Aspery’s lab, where the early work on – where he was doing the early work on x-ray diffraction patterns of collagen, I think. I’ve forgotten exactly what he was doing, but it seemed very dull, and I didn’t consider a post-doc there. What a mistake to think that x-ray diffraction was dull. It became so interesting. This is the only reference I can find in any of my studies to even thinking about x-rays. It’s just a note on paper that I wrote.
I find I had one tutorial essay on ascorbic acid, vitamin C. Interestingly enough, that was a topic that was given in the final examination of my chemistry degree and I remember answering it with great delight, because I’d always found ascorbic acid interesting, and written about it in my essays.
A similar folder on the structure of glucose is an essay for my chemistry (?) or tutor.
The next one is a very special one for me, in which I wrote an essay on the Pauli Exclusion Principle and the period table. And this was with an early tutorial with Ronnie Bell, and my recollection of it is very dramatic. We got about halfway down the first page, when there was something that I didn’t understand couldn’t justify, and he spent the rest of the hour drumming into Smithies’ brain that you never write down anything that you don’t understand and that you can’t justify. I’m going to see if I can see what it was. It’s a pity that we never got to read the whole of this essay because I would’ve liked to have read to Ronnie Bell my final sentence: “once these configurations are known, many before incomprehensible prophecies become reasonable, and the whole table becomes a logical conclusion of the principles guiding the addition of electrons to charged nuclei.” I just loved the Pauli Exclusion Principle and the period table. I never got to tell him about it.
I really question whether this was for a tutorial or not, but I have one collection of writings on the chemistry, O. Smithies, on the sterols, and it’s many, many pages long. About 26 double sided pages, so it’s 52 pages long. I doubt if I could have read that in a tutorial, so it must have been something I did to learn or teach myself with. These notes must have been for teaching myself, because I have one chemistry, again Smithies, the synthesis of indigo and its use and derivatives. And Vindol (?). And then I have one similar one on tryptophan, its synthesis, metabolism, and derivatives. I like this one that I found, chemistry O. Smithies, polymerization, and it talks about polymers, and this one is 29 double sided pages, so that makes it nearly 50 pages on polymers. I’m not surprised because I loved polymers already, because in high school, in the grammar school, we were just beginning to understand that polymers existed, as it were. Fascinating time, the beginning of understanding of polymers.
I always enjoyed the problem related to solubility, and it’s obvious that I must have enjoyed it from my notes on this. I have one of the chemistry notes on the factors governing the solubility of non-electrolytes. There are 38 double sided pages on that topic.
An essay on the alkali metals, their structure, similarities, and differences. I enjoyed that one too. It’s not very long, but I end up with “so we can explain many of the prophecies, similarities, and differences of the alkali metals in terms of known principles, and their known structure, though it is not to be expected that every detail will be perfectly explicable in general terms.” A little bit pompous.
I was wrong about not having studied anything to do with x-rays, because I have about 100 pages on the use of x-rays for investigating crystal structure, starting with theory and then going on page after page on all sorts of things. Structure and its relation to acid base.
There’s a single page here, headed “colloid monograph 1, page 348, Shepherd,” and then it goes on with Lipmann grainless. And this is talking about Lipmann grainless is one of the early methods of making color photographs. It was a very fine grained so-called Lipmann emulsion, and there was floated on the top mercury, and then light went through the back of the film, or it was on a plate, through the back of plate, through the Lipmann emulsion, and reflected by the mercury, made standing waves and so silver was deposited with the separation equal to the wavelength of the light that was being used. So when viewed properly, you could get color images out of this. First color photography ever devised. I spent quite a lot of hobby time trying to make those Lipmann emulsions, to reproduce that color, but I was never successful. But the page is sort of interesting because it gives some recipes, for example, 500 CCs of 10% gel solution, with 1.5 grams potassium bromide per 100 CCs, and 2 grams of silver nitrate per 100 CCs. And talk about Lipmann emulsions. And ripening to increase the grain size, things of that sort. It didn’t work for me but it’s a sort of record of what I was doing when I was playing around.