- Welcome, everyone, to Wednesday Nite @ the Lab. My name is Tom Zinnen. I work here at the UW-Madison Biotechnology Center. I also work for UW Extension Cooperative Extension, and on behalf of those folks and our other co-organizers, the Wisconsin Public Television, Wisconsin Alumni Association, and the UW-Madison Science Alliance, thanks again for coming to Wednesday Nite @ the Lab. We do this every Wednesday night, 50 times a year. Tonight it's my pleasure to introduce to you Dave Nelson. He's Professor Emeritus of biochemistry. He's also the founder of the Wisconsin Science Museum. He's here on both of those roles. Tonight he gets to talk to us about one of the great accomplishments out of our university. This year is the centennial of several things at UW-Madison. It's the 100th anniversary of playing football in the new Camp Randall Stadium, it's the centennial of Wisconsin Public Radio, but it's the centennial of the discovery of the B vitamin family. And we get to hear part of that story tonight. Dave will be talking with us about Conrad Elvehjem, who grew up in McFarland, not too far from here. As I like to say, McFarland is right next to McNearland.   (laughter)   And that's why I have this job.   (laughter)   Dave was born in Fairmont, Minnesota. That's where he went to high school. Then he went to Stanford, undergrad. No, for his PhD, excuse me. Went to St. Olaf's for undergrad. Went to Stanford for his PhD, then he postdocked at Harvard, and then he came here in 1971.  Nobody has given more Wednesday Nite @ the Lab talks than Dave, and nobody has given better Wednesday Nite @ the Lab talks than Dave. This is going to be a great story of the discovery of niacin here on the UW-Madison campus. Please join me in welcoming Dave Nelson back to Wednesday Nite @ the Lab.   (applause)    -  Thank you very much. Thanks, Tom, and thanks to all of you for coming out on a hot night. During the period between about 1885 and 1940, there was a worldwide revolution in the life sciences. And it actually began here. Some of you have heard, those of you who come to this session regularly, about the role of Wisconsin in the discovery of the vitamin process for making active vitamin D. And you probably have heard about the importance of Wisconsin's participants in the development of the drug warfarin, KP Link. But there's a less widely sung and no less important discovery, and I want to talk to you about that tonight.  I'm going to take you through about nine steps, and it may look as if it's a crooked line, but we'll get there. I want to show you how, first of all, in Madison, the discovery was made that there are factors required in the diet that are not among the things that people used to expect to be complete. That is, there are factors that are not carbohydrates, fats, or proteins. We, of course, know now they are vitamins. But I have textbook of nutrition in my office from 1907 in which vitamins don't even enter into the table of contents. Not in the index. So this is a relatively new development I want to talk about how that began here. The revolution that I'm talking about was a sort of paradigm shift, which is always interesting to watch in science. In this case, the shift was from the way people thought about the nutrition of farm animals before, let's see, 1890, and the way they think about it now or have since about 1940. That insight came in part by the separation of foodstuffs into two different categories. Those that were essential to growth and soluble in water and those that were essential to growth and were soluble in fat. They became known as fat soluble A, and A became actually, with investigation, a fraction that contained vitamins A, E, D, and K. And there was water soluble B, which, upon a long investigation, turned out to be several vitamins, B1, B2, B3, B6, B12, and so on. There was, with the discovery of these accessories factors in the diet, a world race. I mean, every lab in the world, it seemed, was trying to figure out what their essential cofactor was. And I'll tell you just a little bit about what went on around the world, but I want to focus here on what went on in Madison, of course.  This whole story comes, finally, to the medical cure for a very serious disease which was rather common in the American south in the period between about 1900 and 1920: Pellagra. I'll tell you more about that later, but it was the cure for Pellagra that was sought and found here in the shape of a compound, a simple, cheap compound called niacin or vitamin B3, which was discovered here by the group headed by Elvehjem.  The other developments that help us understand more fundamentally what the vitamins do took place in laboratories all over the world, and we came to realize that the reason that we need vitamins is that they perform an essential service in the breakdown of our fuels from which we derive energy. And I'll show you a little bit of that later. If there is time, we'll talk very briefly about the discovery of the importance of iodine for goiter also took place here. So this is about 1910. The dairy barn was over here where it still is. It was, in 1910, kind of green, believe it or not. And it was in this barn that the first experiments that started this revolution took place. They were directed by and thought through and brained by Stephen Moulton Babcock, who was one of the first members of the faculty in the College of Agriculture and Life Sciences. And that experiment that he planned and carried out with the help of three others was called the single-grain experiment in which the objective was to test the hypothesis that all you needed to do to make a farm animal healthy was to give that animal carbohydrates, fats, and proteins and enough calories. That was the party line. That was actually in a textbook of nutrition, published by the dean of the college here. But Stephen Moulton Babcock doubted that on the basis of reports from farmers all over the world who had found that not all feeds were equally good. So Babcock planned an experiment to test that hypothesis. And the idea here was that you want to ask if simply providing enough protein, carbohydrates, and fat is sufficient. So he planned an experiment in which he got four groups of cows, young heifers, and they were put into separate categories, one of which was fed all corn. All corn. Another all wheat, another all oats, and a fourth one a third of each of these things. And in order to get the same number of calories and the same amount of protein and carbohydrates from these various grains, they had to use different parts of the plant. So the leaves, the stem, the grain and so on. But they matched things so that the cows are all getting exactly the same amount of what was thought to be the important stuff for nutrition. And then they followed those cows over a period of two years. They watched their weight gain, they watched their milk production, they looked at the health of the calves that they produced, and it turned out that the result contradicted the standard party line in a very striking way. This is the single- great experiment. It was published in 1911. It was done a couple years before that. These are the three people who worked with Babcock, who was, by the way, a fairly old man or middle-aged old man when this was all done. EB Hart was a younger man who was sort of the brains behind this effort. Elmer McCollum, who was a young man who I think we would call an instructor now in biochemistry, and Harry Steenbock was a graduate student. These names all went on to fame. But it was the three of these with Babcock's advice who did the experiment over a period of two years, and they found a very clear result: that the cows fed on corn alone were healthy and their calves were healthy and they gave more milk, better milk, than those fed on wheat or on oats. In fact, the wheat- and oats-fed cows in their second calving gave birth to cows that were born dead. So it was very clear that these three sources of food were not identical. Something was in corn which was not in the other two, and it was unaccounted for in textbooks. So, what do you do? Well, what these three did was to take this not good diet, let's say the oats diet, and asked if there was anything they could add back to it that would make it a good diet. So, for example, they took the regular oats diet and added butter, or in another case added milk. And it turned out that in both of those cases, the diet which was not good, became good. So there's something in milk and there's something in butter that actually are essential to growth and important. And, of course, now the question is, what is it in bu  So these three made that discovery and published it in 1911. And it made the chemical analysis paradigm no longer tenable, and instead we needed to ask with biological assays, what is this cow missing? And the only way to do that is to use essentially a bioassay. You have an animal who is not well-fed, and you figure out what to do to make the feed good. A new paradigm and this paradigm was recognized immediately, not simply here, but all over the world. And as soon as it became clear that this was a way of looking for new kinds of compounds, new kinds of dietary factors, everybody in the nutrition world, all over the world, began trying to identify what these factors might be. Their approach was almost always the same: feed a diet that was not quite adequate and ask what they can supplement it with that made it good and then look what's in that supplement to figure out why it's good. McCollum introduced another important change.  The experimental cows were very expensive. Cows take a lot of space. They take a lot of food, they take a lot of tending. They have a slow turn-around for calves. And so, in general, they were important domestically and the ag school was happy to support them, but, in fact, the experiments were too tedious if you used cows, and McCollum, therefore, went to the dean and asked for a few dollars to buy a couple of cages so that they could use rats in the basement of biochemistry. The dean apparently threw him out of the office and told him that if the farmers of the state ever figured out that the dean was spending their taxes to learn how to nourish rats, there'd be trouble.   (laughter)   So he used his own money, or maybe Babcock's money. He bought a couple of cages, went to Chicago and bought a couple of albino rat mating pairs. This is apparently after having unsuccessfully tried to grab a rat in the barn.   (laughter)   They're not the same as albino rats. So he bought these mating pairs, brought them back here, and they became the progenitors of all of the white rats used in research all over the world for many years. Madison actually had the two largest rat farms in the world for many years. Rats are cheap to feed, don't take much space, have progeny very fast, and because you can have lots of them in an experiment, you get data that are statistically more meaningful. And so it was an important change in the protocol for studying nutrition. Using this idea of supplementing minimal medium, McCollum and a woman, Marguerite Davis, who was his assistant, and I think an unpaid, volunteer assistant, which probably was the way a lot of women were involved in science then, there's a bad, bad history there, the two of them did experiments in which they took the butter or the milk, fractionated it in the ways that were available in 1911, and found that some parts of the milk were of no use at all; they could throw those away. But one part that was clearly important was something that was soluble in lipids, it was a minor fraction so you could purify it and purify it away from other stuff until you had very little but it was very potent in remedying the bad diet. And they published this landmark paper in 1913. The title doesn't sound very exciting, but it really was a major bombshell because it was the first evidence that there was a real compound that was essential to the life and they we didn't know about before that.  McCollum actually had two assistants, both of whom were terrific and both of whom had careers even after he, McCollum, left Wisconsin. He was here from 1907 to 1917. Then he went to Johns Hopkins. Part of the reason for his departure was the town wasn't big enough for Steenbock and McCollum both, and one of them had to go. It was he. But he did take the precaution of turning loose all of his competitors' rats before he left.   (laughter)   That's apparently a true story. Anyway, the two women were Marguerite Davis and Cornelia Kennedy. Both of them published with him, so they were acknowledged as being important contributors here. And although the history is a little fuzzy about this, one or the other of them, or maybe both of them, actually were the ones that contributed the nomenclature fat soluble A, water soluble B.  So, the race began, people began to use this bioassay to look for compounds of interest. And right away the compound that Davis and McCollum had first discovered was further purified to become vitamin A. And McCollum spent a good share of the rest of his days in science looking at vitamin A and related compounds. Also in the fat-soluble fraction was the precursor to vitamin D, and that was taken over by Steenbock who had, of course, been part of this one great experiment too. And Steenbock made the very important discovery that the stuff was turned into an active vitamin and hormone when the stuff, not the animal, but the stuff, was irradiated with ultraviolet light. This was something that was patented here, that gave rise to the Wisconsin Alumni Research Foundation, an organization that has a bank book with two billion dollars in it now, that's billion with a B, and has made a huge impact on this campus where they invest all of the money they make.  Elvehjem and Strong, Strong was still here when I came in 1971, took the water-soluble stuff, and they purified from it the vitamin I want to tell you most about today: vitamin B3 or niacin. This was many years after the original discovery that there was something there. Going from something to an identified compound took nearly 20 years. 

 Esmond Snell, who was a member of the faculty here, took vitamin B6. Henry Lardy, a member of the faculty here, took vitamin B7. And eventually almost all of the vitamins and minerals were touched by somebody on the campus here. The vitamin C, K, and E were looked at by Link, who was a carbohydrate chemist and had extensive notes about vitamin C that led us about the fact that it cured scurvy, vitamin C. But he didn't get there first, and so those notes remain in his notebook. Phillips studied vitamin E. Baumann studied several of these things including K. So there was actually a large community here in the College of Agriculture in the departments of biochemistry and the new Department of Nutritional Sciences that developed from it. And if you look now on a box of vitamins and look at all the things listed on the back of it, almost every single thing on that long list of 20 or so items has been the object of study here sometime, and many of them are still the objects of study. For example, when Steenbock, who studied vitamin D, he was dealing something that had a profound effect on animals, but there was absolutely not the slightest understanding of how that effect was manifest, how it worked. And now we have a molecular description of what vitamin D does at the essentially atomic level. And so is that true for some of these other vitamins as well. 50 years of work has led to that. We were not the only school in the world who's interested in this, of course. There was a hot competition between Osborne and Mendel at Yale. And the group here in the early parts of the 1915-1920 period. In fact, there is a set of letters that were exchanged between the chairman in the Yale department and the UW department that were close to pugnacious. They were trying to be nice between fairly hardened letters. Great entertainment. There is a, there was and is still a privately funded, very well-funded laboratory Rothamsted in the UK. There was a group who began in India and probably came as close as anybody to beating the group here to the punch that, after making the original discovery in India, went back and worked in Utrecht, Holland. There was a group in Cambridge. Hopkins was the head of that group, and he became famous for his work on vitamins. And there were others. So we didn't have the field to ourselves, and during that period, I would say between 1911 and maybe 1920, there was just tremendous excitement in the field. The papers poured out. Every journal you opened from that period has another interesting observation by somebody. Very exciting time. Here, the excitement led eventually not only to an understanding of the nature of the compounds but of their role in curing disease. And if you walk around campus, I'm sure you have walked around and seen these brass plaques. Here are six of them, which I suppose you may not be able to read.   (laughter)   But they are here to tell us that, one, Wisconsin led in the discovery of this paradigm, two, that discovery led to cures for rickets, pellagra, anemia, iron deficiency anemia and goiter. And if we had time, we could talk about all of them, but I'm going to tell you mainly about pellagra.  There was, coming from various places, information that helped one to plan an experiment in those days. There had been for a hundred years the observation in the literature that the disease, the very serious, lethal disease scurvy could be completely cured by fresh fruits and especially by fruit juices from things like lemons and oranges. That was in the literature but there was no explanation for how it did this. There was no effort to characterize the stuff that was in the fresh fruits. As I said, Osborne and Mendel at Yale had used the same basic approach that was used here. Used an incomplete diet. See what you need to add back to it to make it better. Eijkman and Grijns were in India where they were, they discovered by accident that the disease beriberi, a very serious nutritional disease, was essentially caused by people eating most of their food as polished rice. Rice with the brown hull still removed. And it turned out that the reason for this, the beriberi curer was the stuff in the rice husk. And, again, they didn't pursue the stuff chemically. They just said there is something there, so there's a nutritional disease. Both of these were said. Casimir Funk, a Pole, also read the literature, did some experiments that led him to think that there were accessory factors. And he in fact got so far as to guess that they were amines and he therefore named them vitamines. That's where the name came from. The E eventually was dropped.  Hopkins, in Britain, wrote a great book that summarized the work that went back to Aristotle, practically, about all kinds of things that affected the health that came from the diet. And Hopkins was a major contributor in the whole period from 1920 to 1940. Goldberger, whom we'll turn now, was not a scientist in the usual sense. That is, he didn't work in the laboratory. He was a public health physician at the Public Health Service, the US Public Health Service. And he got into this story when, in about 1905, there was a terrible epidemic of pellagra in the south of the US. From a period of 1905 to 1910 it was extremely serious, and it lasted until 1920 or so. So the Public Health Service put one of their best men, Goldberger, on this problem and asked him to see if he could resolve the cause of pellagra.  And the two causes that he examined of course were either it's an infectious disease and you solve that by not infecting each other and staying out of each other's way, or it's a nutritional deficiency in which case you modify the diet. On the bottom list here is another person who figured prominently into the understanding of how vitamins worked but who was not any part of the evolution that I'm talking about today. Warburg was a German chemist. He was the biochemist's biochemist. Won the Nobel Prize for his work early in his life, spent a lifetime of remarkable contribution, and Warburg, in the course of studying the enzymes that carried out the breakdown of sugars from which we get energy, discovered that there was a soluble factor, he called it, that had to be added to one of the enzymes to make it work. And the soluble factor, it turned out, was made from niacin, the vitamin that Elvehjem discovered here. So we finally, with his work, had an explanation of the effect all the way down to the molecular level. Pellagra is a tough disease, and in some places led to a high proportion of a population being sick and many of them dying. The four Ds, diarrhea, dermatitis, dementia, death, usually developed in that order. So the first thing you see, physically, is dermatitis, and it eventually looks as bad as what you see here. In fact, pellagra is from Italian pelle-agra, raw skin. So this disease was occurring at high frequency in certain places in the south, and those places were orphanages, prisons, towns, cotton mill towns, for example, where everybody was poor or nobody could afford beefsteak.  And so those places, those foci of pellagra, became the target for the investigations by both the group that was interested in checking for infection, infectivity, and the group looking for nutritional explanations. Here's Joseph Goldberger. There are several really good books about his life, and they would justify a novel along the lines of "Arrowsmith," I think, now. He made remarkable improvements in the techniques for epidemiology, set the pattern for this for many years, and he sacrificed himself in a way that I'll tell you about in just a minute. But what he did, basically, was to convince the public health service and the states of Mississippi and Alabama to go along with him as he tested the hypothesis that giving these patients a good diet would cure their pellagra. And they, on a small scale, supported this. So he had two orphanages and two prisons that he went in to. It was very common at that time for half the people in a prison to have pellagra. And it was very common for a quarter of them to die from it. So this is no joke. It was a serious business. He didn't have an institutional committee to satisfy, and he therefore did experiments of the sort you couldn't do now. But he got the results that made the whole thing seem now, in retrospect, to have been worthwhile. He went to these prisons, first of all, took careful notes about what the people there were being fed, and it was soon apparent that the prisons and orphanages in the south at this time had a diet that was very rich in corn and very poor in protein-rich things, like beans, peas, meat, liver and so on. That was the sort of universal finding in all these places.  He also found that the staff, in these orphanages and prisons, never got sick. And, of course, it's because they ate their lunch someplace else. They weren't being fed corn every day, every hour.  So, he did the logical experiment. I think there were something like a hundred children in each of two orphanages. He provided them with really good meals. That is breakfast with eggs and milk, meat for several of the meals in the week, and very quickly found that the kids that were sick immediately responded. The rash that's so characteristic disappeared. If those people had reached the stage of a dementia, even the dementia was reversible. So this is really a pretty dramatic result. At the time, there was a powerful lobby that wanted the other answer. It wanted to believe that this was an infectious disease. And as far as I can figure from reading the history of this period and the stuff about Goldberger, the problem was that the wealthy people in the south, Mississippi and Alabama particularly, valued their reputation for being visitor heavens. And they didn't want the word to get out that poverty was causing illness in their population. So they actually grubstaked another committee to go out and investigate the same question, and that committee came to the other answer, namely that this was an infectious disease, which forced Goldberger to try even harder. And he eventually got the governor of Mississippi to let him work with 11 prisoners in a long-term prison setting with the deal being if they would eat everything that Goldberger gave them for a year, they'd go free. A nice trade-off. And they all managed to do it. Although, when I read the composition of the diet, I don't know how they did it. But in any case, the diet had things that were good for them. He had another group to whom were not showing signs of pellagra, and he fed them an inadequate diet and they developed signs of pellagra. So it certainly looks as though he's the one who's got the data. But to be on the safe side and to show how seriously he believed his own results, he held what the television calls the filth party. And this involved a small group of people, his coworkers in the Public Health Service, his wife, himself, ingesting in various ways, swallowing or being injected with, the scabs from pellagrans, the blood from pellagrans, the feces. And I don't know how they got around the problem of blood types, but they actually injected five mills of blood from somebody with pellagra into themselves, including Goldberger and his wife. That's serious support at home, I'd say.   (laughter)   And none of them, none of them developed pellagra. The other committee that I was talking about, by the way, is the McFadden-Thompson Committee, and they eventually faded after he came through with the hard data. Now, at Madison there was a group of four who took up the problem of the water soluble vitamins that had been discovered in the early 1900s. And these two led the group that discovered niacin, the vitamin that cures pellagra. Conrad Elvehjem eventually became chairman of the department, dean of the graduate school, president of the university, and died young. Actually, he died literally in office. Frank Strong was a younger man who was with Conrad Elvehjem in these studies. Elvehjem was a nutritionist, Strong was an organic chemist, and the two of them got together to do what they could to purify the anti-pellagra factor.  They published this discovery in 1937, and I have actually got on the screen here the entire paper. The one-page paper that put this bombshell on the world lines. There are two things in it that I think are really very striking. A single dose of 30 milligrams of nicotinic acid, that's niacin, gave a phenomenal response in a dog suffering from black tongue. These dogs were on the point of death and they immediately started to be better and came back completely. 30 milligrams, if you have a piece of, if you have an aspirin tablet in your hand, that's 350 milligrams. Imagine cutting it into 10 pieces, taking one of those little pieces and giving it to a dog and seeing a dramatic change. These things are potent, and I'll come back to the explanation for why they are so potent. The other thing that's interesting here is their statement: "The observation that a deficiency of this material "may be the cause of black tongue." I'm sorry I didn't, I left something out here. A veterinarian who treated lots of dogs had discovered years before this that there was a disease in dogs that mimicked pellagra in humans called black tongue. It affected all the things that are affected in humans. The mouth, of the dog particularly, developed sores. And it turned out that a dog with black tongue was the experimental animal that Strong and Elvehjem used. They had the dogs in the attic of the building right across the street. They gave them a diet that was inadequate. The dogs developed this disease, and then they added niacin back and cured it just like that. So, the observation that a deficiency of this material may be the cause of black tongue is most interesting. There's only one other paper that I know of that has this kind of low-key announcement, and that's the paper by Watson and Crick that announced the structure of DNA. They said in their one-page paper, "It has not escaped our attention..."   (laughter)   And the same thing here. I guess maybe it's a Midwestern tendency not to blow their horn. But they didn't have to. The word was out. They immediately corresponded with six different physicians around the country, all of whom expressed interest in treating their own patients with stuff. And Tom Spiece is the one whose publication came out first. He managed to cure human pellagrans with very lose doses of niacin. By low dose I mean milligram quantities. And the story was pretty well complete.  The people involved in this were appreciated, not just here, but in the world. The Nobel Prize nominations have always been secret, but the Nobel people have just, in the last year, allowed you to see everything that took place before 50 years from now, 50 years back. And this period, of course, is now open in their archives. So Elvehjem was nominated nine times for the Nobel Prize, twice in one year. Strong, the organic chemist who really determined the structure of niacin, was nominated twice. Madden and Wolley, who were the graduate students involved in this discovery, were themselves actually nominated. And I think in the case of Wolley, the nomination came as much for the work he did after Wisconsin as before, but, in any case, they were widely, highly regarded. McCollum was nominated six times or seven times. Steenbock twice. And Karl Paul Link, who actually had had a role in the determination of the structure of niacin, when they got the purified stuff that Frank Strong as a chemist had developed, they needed to do an analysis of the carbon/hydrogen/nitrogen content, and KP Link's lab did that. Link later made other important discoveries that led to his nomination for the prize five times. So it's a really remarkable group of people.  None of them won the Noble Prize, and part of the reason is that the other groups, that were studying nutrition, trying to run down these factors, were no slouches either. So, Eijkman, whom I said had figured out a way to study the vitamin thiamine, won the prize. Hopkins from the UK. Henrik Dam determined the structure of vitamin K. Each of these people made an important contribution either in the discovery of the vitamin itself or in its isolation or in its actual chemical structure, synthesis or structure. And you can see that during that period of about 19, what is it, 1929, I guess, until about 1940, there was a lot of hot action in the field of vitamin chemistry and biology. 

 So, to recap what I've said, the discovery of essential factors really was something that took place in Madison. That's in red. The paradigm shift that led people to approach nutrition from a different angle, that was from here. It quickly was adopted elsewhere and used. The separation of vitamins, quote, into fat soluble A and water soluble B surely was a Wisconsin development, and it was the very beginning of a long series of chemical studies. There was the international effort to identify factors. Pellagra was defined, finally, after Goldberger's work as a nutritional deficiency, and then the structure of niacin itself was discovered here. The effectiveness of niacin in curing black tongue and pellagra was initiated here. And the work on this vitamin fell together with and took place almost at the same time, 1935 about, when the biochemists in Europe, especially Warburg, Otto Warburg, were figuring out that the cofactor that there were enzymes needed to break down food was made of the same stuff that was curing pellagra. And it became clear, there were two things that came out of this that made sense. One is that chemists and biologists had missed the presence of vitamins earlier because nobody had instrumentation sensitive enough to detect such small quantities of these things. And the reason that they were present in such small quantities, these cofactors, is that, like enzymes themselves, they didn't get used up. If you have a hundred grams of sugar in your hand and ask your body to digest it, it'll do it all right and pretty fast. So a large quantity of stuff is used, but to do that, enzymes that are present in such small quantities by comparison, you can't see them do it. And the reason is that the enzyme keeps cycling. It does it, does it again, does it again, does it again. And the cofactors for the enzymes, similarly, recycle. So you don't need very much. Some of the cofactors, some of the vitamins are needed in the range of micrograms. You can't see a microgram in the palm of your hand. So they're extraordinarily potent, but that means they're present in living cells at low levels and that's what it made it so tough to discover them.  Okay, so there is, let's see, there is time. So let me just tell you a little bit more about a couple of things here that figured into this story that I've told you. One was the discovery by Buchner in the turn of the 20th century that yeast not only could make alcohol from sugar but broken down yeast, yeast completely destroyed so their guts are spilled out, their guts convert glucose into wine. And this cell-free fermentation allowed the biochemists to go in there and start picking and choosing things and putting together the sequence in which the sugar was broken down in what turned out to be 10 steps into its product. So Buchner actually, who won the Noble Prize for this discovery, opened up the whole of biology to biochemical approaches. And now the biochemists could go in and define pathways. Otto Warburg I've said was one of the people who did that. He showed that there were 10 steps that all of us, ants, elephants, people, alligators, we all do it the same way, and for each of those 10 steps there's an enzyme. For one of those 10 enzymes there is a cofactor, which Warburg discovered as something that was water soluble and had to be added back to make the fermentation go in the test tube. So, he was zeroing in on this as a chemist, and everything fell together. When they looked at niacin, they looked at the stuff he purified, and it was the same stuff. Suddenly it was clear why these vitamins were so essential. And that's true not just for niacin, all of the vitamins do the same thing. They all function catalytically. They all are essential to normal metabolism.  And their lack in the diet is seriously felt. In the years since Warburg started this work, scientists have discovered that there are more than 400 enzymes that all use niacin as a cofactor. And so it's no wonder that if you don't have niacin, you're hurting.  Here's a picture for those of you who like to see the structures, but, basically, here's niacin over here, and if you just look at this hexagon with the nitrogen. You see the same thing right there. That's the business end of the cofactor, which is called NADH, and the name of this compound comes from the structure of nicotine, which is otherwise in no way related to this story. Nicotine happens to be something that you can use to prepare niacin. You break this bond and now you have that same hexagon with nitrogen. But, except for that structural resemblance, nicotine has nothing to do with niacin. Just a couple of slides about one more serious disease that was cured by research that took place here in that same period that we're talking about. Goiter is something common in, it was common in the Midwest and the Pacific Northwest. It resulted in the swelling of the thyroid gland, which is right here, and the swelling could be quite extreme, as it is in the case of the man that I'm showing you here. The problem with goiter is that the thyroid gland, which is supposed to make a hormone called thyroxine, can't. And because it can't, it grows hoping if I can get bigger, I can do it. And eventually you have this enormous thyroid, but it still isn't working. And so the patient still is ill from the lack of the product of this gland, the normal product thyroxine. Don't worry about the structure here, but I want simply to show you that thyroxine has four iodine atoms in it. One there, one there, one there, one there. This is very unusual in biology. I can't think of any other compound that's just so full of iodine. If you take a swig of iodine, it'll just go straight to your thyroid gland. If you've ever had therapy when they're trying to work on your thyroid, they'd use spoonfuls of iodine. So thyroid hormone contains iodine, and the people who get goiters get them because their diet doesn't include iodine. The ones in the Midwest weren't getting any seafood. And the seafood, because the ocean is full of iodine, seafood provides iodine. So, there was sort of a plague of goiter. And Hart and Steenbock, Hart, the professor, Steenbock, the student, discovered that the problem was simply a lack of iodine. And something like two billion people still live without iodine, lived in parts of the world where there is no sea water available and no iodine in the Earth to speak of. I was surprised but I actually confirmed this. This is, the lack of iodine is the leading preventative cause of intellectual and developmental disabilities in the world. A very common, very serious problem. And, shockingly, it could be cured by this kind of thing. 150 micrograms, which I've said is barely visible in the palm of your hand, daily, costs a nickel a year to solve this problem. And the fact, that the world still has people suffering from goiter, is criminal.  Hart not only discovered this role for iodine but figured out a way to solve this very easily, and that is if you simply supplement some food that everybody eats with iodine, that should solve the problem. It turns out that everybody eats sodium chloride, table salt, that he figured out a way to get iodine into the table salt in such a way that it would stay stable, which wasn't trivial to do. And now when you buy salt, it always says, as this one does here, iodized salt. So you see very, very infrequently goiters.  Okay, then let me just close by telling a little bit of what happened to Elvehjem after this initial important scientific phase of his life. Elvehjem must have been an amazing organizer because he was able to be the chairman of the Department of Biochemistry during this incredible active period of the 1920s and 1930s and to be the graduate dean and then eventually to be the president of the university. And he kept the research group going. He was responsible for a lot of really important changes around here. For example, it was his work that resulted in the establishment of the Enzyme Institute, a unique organization which for many years distinguished the University of Wisconsin. He trained 88 doctoral students, which is just inconceivable. And he died at the age of 62. He very likely would have won the Nobel Prize if he hadn't died early. This is a portrait of him by Aaron Bohrod, who was the university's artist in residence. This rosemaling is no doubt his Norwegian background. This is the, the winged victory of Samothrace, is the statue on top of the Lasker Award, which he won. The Lasker Award is usually the last thing that happens before you get the Nobel Prize.  I might say that KP Link, whose son, Tom, is right here, won two Lasker Awards.  Here we have somebody who clearly has pellagra. Okay, thank you very much, and I'll be glad to take questions if you have them.   (applause)