University Place  Dave Nelson Groundbreaking Discoveries at UW-Madison  May 29, 2013 UP880  cc >> Good evening, everyone, I'm Cassie Immel from the Biotech Center. This evening, Dr. Dave Nelson will begin our saga through the vitamin research at UW-Madison. Dr. Nelson has been an emeritus professor at the UW since earlier this year, and has maintained his professorship from 1971 to 2012. He received his Bachelor of Science at St. Olaf, and his PhD at Stanford Medical School. Dr. Nelson is an integral part of the Biochemistry Department as the unofficial, maybe official, historian. Through his part as the historian, he has acquired, through one way or another, many different tools and science equipment that has been used by pretty important scientists throughout the years. A few days ago, I went on a tour to one of the teaching labs so I could eventually use it to teach a group of students. The lab manager took me over to a lab bench that had a piece of machinery that was broken down into different components. She briefly explained that Dr. Nelson uses this lab bench for his museum pieces, and he attempts to restore them. This talk highlights Dave's innovation as a precursor to his upcoming public course that offers participants and spectators an opportunity to hear about UW-Madison discoveries then and now. 

So let us begin this journey of vitamin research, as Dr. Nelson restores our awareness of these very important molecules. Dr. Nelson. [applause]  >> Thank you, Cassie. Welcome to all of you. As you see, I'm going to talk about history of some research on this campus tonight. I'm going to divide the talk into two halves, partly because I didn't submit a title to Tom Zinnen, and he, of course, made one up for me... [laughter] and obliged me to do something that I hadn't actually planned to do, but it'll be fine. I'm going to talk first about the facts that this day, that is, in fact this Saturday, is the 100th anniversary of the discovery Vitamin K on this campus, which began a long series of very productive research here and elsewhere, that eventually revealed all of the vitamins and changed the way we think about vitamins' role in biochemistry. So I'm going to talk about that in the first half of the talk. Then I want to turn to a discussion of a new course that some retiring professors in the College of Ag and Life Sciences have been offering now for two years, a course in which we hope to conserve some of the history of the university, especially in the College of Ag and Life Sciences, and to spread it around a little bit to the public and to the students who walk around these buildings, whose names mean nothing to them because they don't know any history. 

So, that's the order for today. First, a little bit about the discovery of vitamins. Every day for 30 years, I walked by this bronze plaque in the entry to Biochemistry, which is the plaque that commemorates the contributions of Stephen Moulton Babcock to the college and to nutrition in general. This guy was a giant in the early years of the College of Agriculture. He came here in the mid-1880s as essentially the first professor in biochemistry at a time when the college was very small, and the college had the very clearly assigned role of providing farmers information that would help them more effectively farm. Babcock's first assignment when he came here was in fact to help farmers do a specific thing, which I'll show you in a moment. This is the way the college looked in that general period of time, a little after he came here. Very small. Very few buildings. The building we're looking at here is King Hall. 

That's Ag Hall up there, so this must be somewhere down by the lake, where the photographer is standing, looking up towards Ag Hall. This is the UW Dairy Barn, which still stands. It is, in fact, an historical site, and can't be torn down. The Dairy Barn was the site of the research that I'm going to tell you about, which led to the discovery of vitamins. It still stands, although it's been altered substantially and added to, but you'll see all these components if you go there now. When Babcock was hired by Dean Henry, his first assignment was to solve the problem that farmers had encountered. When they realized they had been selling milk to the dairies, it was too easy for everybody to cheat. Milk was originally sold by the pound or the gallon, and that could be easily fixed by just adding a little water to it. So there was no real standard for how high quality the milk was. Babcock's job was to solve that problem, which he did over a period of a couple of years, in developing a test that became known as the Babcock Butterfat Test. 

It employed a very simple device. I can hold it in my hand. It was a centrifuge with special calibrating bottles. The farmer just put a certain amount of milk in the bottle, added sulfuric acid to it, waited a bit, centrifuged this so the fat that was in the milk would float to the top. Then he used the gradations on this long, thin top to measure off the concentration, the amount, of cream or the fat. With this, the farmer who kept honest, the markets could finally base their prices on things that mattered, and Babcock became world famous. That is not, however, what I want to talk about tonight, but rather his second big undertaking here, which is more or less on his own this time. He wasn't being ordered to do this by the dean. He explored a question which had bothered him for years before he came to Madison, namely what constitutes a really good feed for farm animals. There was sort of a general feeling and in fact the dean of the college here, Henry, had written a book to express this feeling, that as long as you gave a dairy cow enough protein, enough fat, enough carbohydrate, and enough calories, that cow would be fine, regardless of where those components came from, which grain for example you fed. 

This was the idea, the paradigm, that chemical analysis of food would allow you to evaluate its goodness in farming. Well, farmers knew better. They had whispered to Babcock for years that this wasn't quite right, that there was not a good correspondence between the results of feeding animals different feeds, although they were all getting the right amount of protein, fat, and carbohydrates. So, Babcock set to test the hypothesis that there was something else in food, animal feed, that wasn't carbohydrates, fats, or proteins. It was courageous of him to do this, because his dean had written the classic work on animal feeds, and he had clearly opted for the chemical analysis hypothesis. So, Babcock did what is now called the Single Grain Experiment. Here he sits in his old age. He's in front of an analytical scale that allowed him to measure small quantities of materials. That is actually quite characteristic of what he did. He did a lot of chemical analysis of foods. 

He developed a group, which started with E.B. Hart, who was then a long-time professor in the Department of Agricultural Chemistry here. Hart, like practically everybody that was hired into the department then, had grown up on a farm. He had a PhD. He had gone off to Europe, as most biochemists and chemists did in those days to sort of finish their education. He had worked before he came here at the New York Agricultural Experiment Station. He'd already developed some tools and some ideas about how he wanted to operate here as a faculty member. He came at the time Babcock was eager to test this hypothesis. Babcock and he put their heads together, and they found two ready helpers, one of whom was Elmer McCollum, also a farm product, with a PhD from Yale. He had a degree in agricultural chemistry, the name biochemistry wasn't adopted until substantially later. McCollum came here as I think a sort of glorified post doc. 

I think he might have been called an instructor, but he was paid poorly. Harry Steenbock, who's just a little bit younger than McCollum, came here as a graduate student. It was Hart, Steenbock, and McCollum, working with Babcock's direction, that went after this question of what makes a good feed. Each of these people had remarkable careers. I note here that Steenbock would stay here for his whole life. He published a large number of excellent papers, trained a huge number of graduate students, and made a big impact on the campus in several ways. Babcock's experiment was simplicity itself. He took four groups of cows. They were heifers. They were paired. 

They were fed exactly the same amount of carbohydrate, fat, protein, and calories. But those things came from three different sources. One pair of heifers got those things strictly from corn. In order to balance carbohydrates, fats, and proteins, they had to use different combinations of the leaves, the kernels, the stalks, and so on. But they could arrange to feed these pairs of heifers the right amount of stuff as all corn, all wheat, all oats, or a fourth pair of heifers got one-third of each, corn, wheat and oats. What made this experiment especially valuable was that they had the backing of the dean and could actually invest the time and the money to follow these animals for a long time. This was not going to be a short-term experiment. They did. They followed them for two years or more. They found at first that the source of the food didn't make much difference to the animals, but slowly but surely, they began to reveal differences. 

And when they calved, the calves had different fates. In some cases, the calves were born healthy. In some cases, they were born sick, and in some they were born dead. Then they followed a second round of calving. Again, they checked the health of the mother, no longer a heifer, and the calves. All the while, they were collecting samples of milk, measuring the butterfat content to see whether the quality of the milk that these cows were producing, whether it changed with the different foods. If the old paradigm was right, all these cows should be equally healthy, but they weren't. Nor were their calves. There were quite remarkable differences. Those differences were described in a very famous publication, Bulletin 17 from the Wisconsin Agricultural Experiment Station. 

That was published in 1911 by Hart, McCollum, Steenbock, the three I just mentioned, and a fourth, Humphrey, who was in Animal Sciences. He actually helped and was invaluable in helping to keep the animals as healthy as he could. This Single Grain Experiment showed that cows, heifers grown on all oats eventually, slowly deteriorated, and their calves were not healthy. Those grown on a mixture of each of the three grains were themselves not healthy, nor were their calves healthy. Those grown on all wheat had very unhealthy, or born dead calves. But those grown on all corn were just fine. The cow was fine. The milk was fine. The calves were fine. Everything was fine. 

So clearly, the old paradigm for deciding whether the food was good or not was not good enough. Something in the corn is providing something these cows needed that the other grains didn't provide. That meant that there had to be a new way of looking at food to decide whether it was good or not. Instead of chemically analyzing it, you had to try it on the animal to see what worked best. This is a bio assay. That was a huge paradigm shift. Suddenly, everybody at the college here, all the other agriculture experiment stations around the country, and for that matter in the world, began to use this basic experiment that Babcock had dreamed up, and that Hart had supervised, to ask with different animals, sheep, pigs, cows, and so on, what was ideal in the food. The idea was always to give the animals some sufficient diet and then add stuff back to see what you could add back that could make the diet fully adequate. In the case of the Madison experiment, what was added back was either butter or milk, or cod liver oil, or some fraction devised from those foods. It turned out that all three of those things, butter, milk, cod liver oil, when added to an insufficient diet, made the animals healthy again. 

This is a very expensive experiment. It took a long time. Like I said, it took two or more years just to follow these things. McCollum was smart enough to realize that he would never win the race to find these critical elements, which we now know were vitamins, if he used cows. So he went to the College of Agriculture dean and said I want to build some rat cages in the biochemistry department so I can use rats as my experimental animals. Apparently, the dean was not happy with the thought that he would be spending Ag School money to make rats healthier. So he kicked him out. What happened was finally McCollum went to Chicago on his own, with a few dollars of his own money, bought a few pairs of mating domesticated rats, not the kind that live in a barn, but the nice white fuzzy ones, and began to use those in his research. That was actually a tremendously important change. That change was adopted elsewhere, too. 

For a long time, the two largest rat farms in the world were located in Madison, producing experimental animals for use all over the place. These rats were cheaper to feed. They took far less space. They had a short life cycle. The numbers that could be included in the experiments meant that they the experiments would have good statistical significance, which you just couldn't hope for with cattle. Here's the publication that came out of McCollum's study. I note here right away that McCollum worked with Margaret Davis, a kind of mysterious figure. Several of us were talking about this a couple weeks ago, wondering if there was anything known about her. At that time, I only knew that she had worked with McCollum during the ten years he was in Madison, and then disappeared, only to re-appear as an 80-year-old woman, long since retired. We've now learned some more about her, because one of the students in the course I'm going to tell you about dug into this and found the history. 

But notice here, June 1, 1913, the title isn't very revealing to us, but to people who were in the field at that time, it meant everything. "The Necessity of Certain Lipids in the Diet During Growth." It was done with rats. It was a very convincing experiment. It began the race for finding the factor, or as it turned out, the factors in good food that could be used to supplement bad food to make it good. Here's Margaret Davis. The only picture I've seen of her is this one taken late in her life. She was born in Racine. She grew up in Wisconsin. Started school here and finished her bachelor's degree at Berkeley. Worked as an invaluable colleague of McCollum's in these critical experiments. 

Then she actually went off and started at Pharmacy school at Rutgers. She worked for a while at Squibb. She came back here and established the UW Nutrition Lab, something I'd like to look into more. But in any case, she had a productive career. She didn't move with McCollum when he left Madison after ten years here to go to Johns Hopkins. McCollum represents an interesting transition in that he left the College of Agriculture, where he had done landmark experiments in nutrition, to go to a College of Medicine, where he would now be using those same techniques and the same information to care about human health, not animal health. He lived a long life, and in his old age, he looked like a retired bank robber. [laughter] So the publication of this paper, exactly 100 years ago, opened the flood gates. And from now on, people tried all sorts of techniques for fractionating good food to find out what it was in there that was essential to make bad food good. McCollum used a technique of trying to separate fatty stuff from water soluble stuff. 

He did succeed in getting to fractions, each of which when added back to poor food made it good. One of them he called Fat Soluble A, and that it turned out became not only Vitamin A, but E, D, and K. The other he called Water Soluble B. That became to be called B1, B6, B12. Those were also vitamins, so he actually had discovered that there was not just one vitamin, but several. Hart, who participated in the original grain experiment realized that in addition to the things that we've been talking about, carbohydrates, fats, and proteins, animals almost certainly needed minerals, that is, inorganic things. To try to zero in on them, he took the good food and ashed it. He treated it so harshly that it was entirely oxidized, and all that was left was inorganic stuff, products like zinc and copper and iron and nickel. He found that there was something in the ash material that also could be added back to make food better. So eventually, what fell out of this work over the next ten or 15 years, is McCollum focused on Vitamin A, and he gets credit for its discovery. 

Steenbock, who'd been an original participant in that early experiment, latched onto the fact that Vitamin D could, with food, irradiated with ultraviolet light, would produce Vitamin D that cured animals of Rickets and people. Elvehjem and Strong looked at the water soluble part of this material and found a vitamin called Niacin, which it turned out was the missing element in the human disease Pellagra. So in discovering this, they solved the problem of Pellagra completely. Pyridoxal phosphate, or Vitamin B6, was discovered by another Madison scientist, Snell, and eventually, Vitamin C, K, and E, copper, iron, zinc, iodine, selenium, fluoride, all of these things were studied by one or another of the people here in those early years, and in fact, there are still people here who are following up on these early studies by asking in greater and greater detail, how does this stuff work. In many cases, it's looking at the molecular details of how a certain dietary component improves health. So, if you wander around the campus now, the CALS end of the campus...  You'll see these brass plaques that were put up by the UW Foundation some years ago. They're actually interesting, because they are put by the building where the work took place, and they describe succinctly what the work was. What you see here is that the discovery of vitamins and trace minerals is attributed to Hart, who was really the organizer of that experiment. The discovery of Vitamins A and B are attributed to McCollum and Davis. 

Vitamin D production to end Rickets is attributed to Steenbock. Treatment of iron deficiency anemia was done by several investigators, including Elvehjem, Steenbock, and Hart. The discovery of Niacin to eliminate Pellagra was Strong and Elvehjem. Strong was still here and alive when I came in 1971. And for the cure for goiter, which was very common in the area around here, where people didn't eat seafood, and therefore didn't get the iodine from sea water, goiter could also be cured, as they discovered, by simply providing very inexpensive iodine in the diet. When you buy salt now, it's iodized salt, and that's why you don't have a goiter. The College of Agriculture, in a very forward thinking move, actually hired an artist, who was an artist-in-residence for the College of Agriculture. His name was John Steuart Curry. He traveled around the state and encouraged farmers to join efforts to do art together, to collect art. He really wanted there to be a vigorous cultural community of artists among the farmers. 

He succeeded to a remarkable degree. There's a whole set of history there that we could talk about if we had the time. This is the painting, the mural, that he painted in the old Biochemistry Building, straight across from us now. If you walk into that building and walk all the way down to the end of the first floor, you'll find this Curry mural. It depicts the Social Benefits of Biochemical Research, and it's talking about the period that I just I've just talked about now, so you see here on the left, you see a boy with the kind of crooked knees that typify Rickets. He didn't have enough Vitamin D. The animals don't look so great, either. On the right, the animals and the people are all well and happy, and their legs are straight. They're profiting from the benefits of research. In the back row here are the people who did it. 

It's kind of interesting to speculate exactly who's represented here, but I'm sure this is Babcock, the guy with the beard. This is probably McCollum. This is almost certainly Hart. I don't know who this would be. I'd have to look at portraits of each of them, photographic portraits, to see if I can match them up. I think we're pretty clear on at least three of them. There's another room just off the place where the murals are, a room that's usually kept locked, unfortunately, where there is a whole set of murals all around four walls. That includes parts referring to the work of Steenbock. Here he is, with his glasses on to protect his eyes from the UV light. He's shining that on milk to create Vitamin D. 

So it's a very interesting set of murals over there. If you ever wish to see them, and can't get in, get a hold of me. That's the story, very briefly, of how vitamins came to be recognized as important elements of food. And the history of how they were investigated thereafter is a whole large course, not a single lecture. But it was an interesting and very important beginning here in Madison, which put the university on the map internationally. Now I want to switch to talk about the second of those topics I announced, and that is a course that came about after a group of retired professors in CALS, got together a little more than two years ago, in October, 2010, called together by Bob Kauffman, who is a professor emeritus in the Animal Science Department. When we were all gathered, Bob said to us, you know, when we leave the scene here, nobody is going to remember any of this history. We know where all the pictures are hidden, where all the stuff is stashed under the steps, and when we die or leave, it'll be gone. So he said, what can we do to try to conserve this glorious history. We decided, among other things, to teach a course that would be offered to undergraduates, but also to the public, in which we use retired professors as lecturers, people who knew the history because they'd made it, and who could talk about it passionately, because it was theirs. 

We decided, therefore, that that would be part of the course. We wanted, also, to make sure that the course emphasized that the work begun in the early 1900s continues today. So for example, the work on Vitamin D that started in 1915, is still a major area of research on this campus now. It's true for many of these other topics that I have covered. So we wanted to correlate the old work with what's going on now, so we decided that the format that could accomplish that was to have, on Tuesdays, a lecture on the history of some development in Madison, in the college, and then on Thursday, a lecture by a current professor about his or her own research that was derived from the old research discussed on Tuesday. Then on Thursday evening, after the Thursday lecture, we had pizza together, and we had a hands-on lab, which I'll tell you a little bit more about in a bit. It was a lot of fun, and we've done the course twice, with results that satisfy all of the old guys that are here lecturing, and I think the students are fairly pleased with it, too. So I thought it might be interesting to share with you, to see what kinds of things we discovered about contributions from Madison that none of us even, people like me who've been here for 40 years, knew about. When you talk to outsiders about the university, they think of Vitamin D and they'll think of Warfarin. That about ends the list of things they know about the university. 

That was about the case for most of us, too. So let me spend a few minutes telling you how this went, and some of what we learned from it. The Tuesday history lecture. These ranged all over the lot, because they were from representatives from all the departments in the College of Agriculture. We talked about the historical beginnings, the land grant laws, and so on, that got the college started. We talked about the experiment I just described, and then a whole lot of things, some of which may be recognizable to you, some not. But this is only half of the lectures we've given so far. It turns out that almost every one of them was a really exciting discussion of an important contribution, told by somebody who felt very passionate about it. That's a winning combination. It doesn't hurt that the people doing the talking know what they're talking about. 

That helps, too. [laughter] So just for example, Paul Williams, an emeritus professor in the Department of Plant Path, told us a story about cabbage around the turn of the 20th century in the area near Milwaukee and near where we are. Cabbage, of course, was a critical crop, because cabbage is the stuff you make sauerkraut out of, and there were a lot of Germans around Milwaukee. So, it was important that cabbage be a productive crop. Here are three people, each sort of the scientific father of the next. L.R. Jones, born in 1864. J.C. Walker, born in 1893. Glen Pound, born in 1914. Each of whom carried on the work of his predecessor, all of whom focused on diseases of cabbage, and they were serious. In the late 1800s, early 1900s, a field of cabbage could get completely wiped out if it happened that the soil was inhabited by a bacterium that fed on the cabbage. 

It would wipe out a farmer if you had that problem. Here's L. R. Jones, the one whose picture I just showed you, and he's out in a field which he has been looking for that rare cabbage that survived under these bad conditions. That's the way you find resistant cabbages, or resistant anything. He did that. He looked at lots of farms for these things. Here's an interesting picture that Paul Williams showed us. This is the state, University Board of Regents out in a field of cabbage, looking at the devastation of this field, and noticing that Professor Jones' miraculous strain that he selected grew perfectly fine in soil that was murdering all the other cabbages. Here's another case where this row of cabbage was sensitive. These rows are resistant. The net effect of studying and cultivating the few that were resistant to disease was that strains were discovered that would grow perfectly well in Wisconsin with very high yield and no problems with disease. 

That still goes on. One of the people who taught for our class this year was Amanda Gevens, who's also from Plant Path. Here's a picture of her in 2009, out in the field with the farmers. They're trying to figure out whether there was something they could do to help productivity for that year. A second crop that I never associated much with Wisconsin, but really has a long and important history here is alfalfa. When, after the Civil War, Wisconsin agriculture turned from wheat to milk, that meant that there had to be forage crops to feed the cows in the winter. Alfalfa turned out to be a wonderful crop for that purpose. But the exact growth conditions, the exact time of harvest mattered a lot in how good a food it was. An emeritus professor of Agronomy told us about this story of alfalfa here. He pointed out something that was apparent in lots of other lectures, too. 

That is, that the early days of the college, when it was small and the faculty was small, and probably they all knew each other, there was a lot of going back and forth between departments. There was no inhibition at departmental lines. He said, for example, the alfalfa story involved important contributions from people in all those departments. I can't tell you the whole story, but I can give you the sense of it here by showing you an old slide, this is from a notebook in 1960, in which alfalfa has been grown, single strain, single farm, so it's all the same stuff in the same soil. But it's been harvested at different times. One crop has been harvested during its vegetative growth, another at its first flowering, a third at full bloom, and a fourth later when the seed pods are forming. This was used as feed for dairy cows. The dairy cows' milk production was monitored, as was the gain in weight of the calves, in this case. Look at the difference. The same crop, harvested at different times, can either give you 45 pounds of milk a day or four. 

That kind of a difference is the difference between going broke and being wealthy on a farm. You see why farmers were happy to have the university dealing with these questions, because they really had significant financial impact. The third piece of research that I had never known about took place in what used to be called Agricultural Engineering. It's the story of the development of a forage harvester, that is, a machine that could cut, chop, and store forage like alfalfa. This was told by Ron Schuler, who is retired from what is now called Biological Systems Engineering. He showed us the early tool for harvesting alfalfa, and a medium time one where the horse pulled what was essentially just a cutter that would lay the crop down. Then you'd have to come and rake it, then throw it in a wagon. So there were several operations. He showed us how F. W. Duffee, in the early '30s and '40s, developed machinery that did all of those things at once. It cut, it raked, and it moved the stuff up and dropped it into a wagon. 

So that in one operation you had your forage. It's kind of a rickety looking machine, but it turned out that it was a very important design that was taken up by a company that I think no longer exists in the Fox Valley, called the Fox Forage Harvester. This was a sufficiently important step forward in harvesting crops like this so that this guy has brass plaques in honor of his having lived. This is some numbers that we were shown by Ron --. In 1936 there were no machines available to harvest forage. There were 27,000 hay loaders, 13,000 silage cutters, 17,000 binders. The invention of the forage harvester led to everybody using it and nobody using anything else. It transformed farming. Millard Susman, retired from the genetics department, told us a series of stories, each of which could be developed into a whole course, I think. Genetics has a glorious history in both plant and animal genetics, and more recently in bacterial genetics. 

He showed us the buildings that first were occupied in 1930, 1963, 1993. We're in one of those buildings now, the '93 building. Millard briefly described the work of a half a dozen people, all of whom had made really very important contributions. Alex Brink joined the faculty in '22. He was chair for years. He introduced hybrid corn into Wisconsin, which was really a very important introduction. It turns out that hybrid corn would grow places where other corn didn't. They had higher yields. It was more resistant to disease. So it was a wonderful improvement for farmers. 

He also developed a winter hardy alfalfa that wasn't killed by low-snow, low-temperature winters. He did, in the laboratory, work that probably should have won the Nobel Prize for him. He discovered, as a fairly young man, that under certain circumstances that looked like genes were jumping around on the chromosome, moving from one place to another. Nobody believed him. It was such an odd idea. But he kept at it. It turned out that so did another person, Barbara McClintock, at Cold Spring Harbor in the east. She lived long enough to be 83 years old and win the Nobel Prize for work that had been ignored 40 years earlier. Brink, I'm sure, was nominated, but he didn't win that prize. Here's Lester Casida who brought to Madison what is now a really active group in reproductive endocrinology. 

He came here in the early part of the century, in 1934 I should say. His primary interest was in the physiology of cows, because their reproduction is so critical to the dairy industry. He carried out the first successful embryo transplant. This is something that we hear about all the time now, but when he did it it was a remarkable achievement. It was, of course, done with cattle. Here's Henry Lardy who was in the Department of Biochemistry. Henry lived to be 93 and died only a couple of years ago. All of his life he carried on research that had agricultural applications. As a young graduate student, as a first year graduate student, he came on the campus, he was assigned the task of figuring out some way to preserve bull sperm. At that time the most dangerous thing on a farm by far was the bull. 

Yet you had to have a bull because you had to inseminate the cows if you wanted any milk. Every farmer had to have this beast on the farm. Henry was assigned the job of figuring out a way to preserve sperm so that one bull could donate sperm to cows all over the territory, or for that matter, across the ocean. And he did. He found a very simple medium, consisting of egg yolk among other things, and in doing so, transformed the dairy industry. He made millions and millions of dollars for these farmers who now could use artificial insemination, not only to dispose of the bull, but to breed dairy cows that were of high quality when they found a good bull. There's a wonderful picture that I found in the archives of bull sperm being delivered to farms in Wisconsin during the rainy season when the roads were so bad you couldn't drive down the roads. They parachuted sperm into the farms, with silk parachutes. [laughter] Sperm from heaven. [laughter] Neil First, retired member of the animal sciences department, made a huge contribution carrying forth what Henry Lardy and Casida had done. 

He was able to rescue an egg from a cow, fertilize in in vitro, that is, in glass, and then put it back into a cow. This led eventually to the ability to take that egg, add a new gene, fertilize it, put it back in. Dolly, the sheep, for example, you remember from 30 years ago, 40 years ago, came about as a result of these developments. Neal First and Henry Lardy both, for this work, won the Wolf Prize, which is the Nobel Prize in agriculture. I dare say that half of my colleagues here have never heard of the Wolf Prize. It's an example of really important work that is not widely reported or known about. Here's Sewall Wright. Sewall Wright was a world famous geneticist who did a lot of highly mathematical genetics. He was at the University of Chicago as a young man, on the left there. That was back at a time when people who turned 65 had to leave the University of Chicago. 

The UW, which didn't have any such rules, picked him up, thinking he might be able to work for a few years. He worked for 34 years. [laughter] And he did spectacularly important work. He published some of his best papers after that time. Here's Sewall Wright, who I knew because he used to come down and eat at McDonald's every lunch time, and we talked about the history of science when he was there. Here he is talking about his favorite subject, mathematics. One of his experimental animals was the guinea pig. If you look carefully at that picture-- Anything look fun to you there? [laughter] He's using a guinea pig as an eraser. [laughter]  Oliver Nelson, no relation, joined the faculty in 1969 in the Department of Genetics. He was a plant geneticist who developed and produced the first structure map and the ability to really say where genes lay along the chromosome in plants. 

He also tackled the problem of improving corn. When he started his research it was known that the standard varieties of corn grown around here, although they were very nourishing for most purposes, lacked one amino acid, lysine. Therefore they were less then perfect food. Oliver figured out a way to breed into the maize strains that were existent then high lysine content. That of course changed things for farmers again. Suddenly a crop was more valuable. It contained something it hadn't before. He was a very soft-spoken guy who never blew his own horn. He didn't get nearly as much credit for the quality of his research as he should have. Here's Joshua Lederberg. 

He was born in 1925. He was a child prodigy. He went though high school and college. I think he graduated from college when he was 17 and immediately went to graduate school, and there made a discovery that was so important that it won the Nobel Prize for him. As a graduate student he did this. He came to Wisconsin in 1947 to join the genetics department. He came with a problem that was new to the campus, and in fact, pretty much new to the country. Namely, the genetics of bacteria. People had for years been interested in the genetics of animals and plants in the hope that they could improve the varieties of animals and plants. But bacteria hadn't been thought of in these terms. 

Lederberg discovered that bacteria, like plants and animals, exchange genes, and can gain or loose genes by this process. He realized that this offered a huge advantage to people trying to understand basic genetics. He therefore started a program here of looking in detail at the genes and the genetics of the bacteria. This is Esther Lederberg, his wife, who was also a wonderful scientist, and was also a student here while Joshua was on the faculty. She did important work on the viruses that infect bacteria. He actually started the Department of Medical Genetics. Until then the department here had been agricultural genetics, or breeding genetics. Now, from the time of Lederberg, the two entities came together, medical genetics and agricultural. He won, for his early work on bacterial genetics, the Nobel Prize. Here he is as a young man. 

This is Jim Crow, another wonderful geneticist, whom I haven't time to talk about tonight, and president of the university. The story that Millard told us was that Lederberg, when he won the Nobel Prize, gave the medal, the big, gold medal, to the university, to UW. And somebody lost it. [ohhs] It still hasn't been found. It's in some cardboard box some place in the basement of some building. This is Oliver Smithies. This is now modern era. Smithies came in 1960 to genetics. He developed a technique for separating components of living organisms, extractions of living organisms. It's called starch gel electrophoresis. 

But in the course of doing those experiments he noticed something that wasn't right in some of his experiments. He pursued that. To make a long story short, he figured out how to get genes into animal cells. That's a capacity that has made all kinds of important changes in the way geneticists and medical geneticists operate. These terms apply to the details of what he did, but the important thing is, because of the work he did, it's now possible for a laboratory, at some cost, to make a mouse that is exactly like it's siblings expect it lacks one specific gene. This is an incredible godsend. Now you can ask what that gene does in that very well controlled background. He left here in 1988. He won the Nobel Prize after leaving, but the work that he won it for was done here. Millard showed us that he was also an avid glider pilot. 

That's what that bottom shows us. Okay, so here is another interesting case of a research project that started as a very practical one and developed into a very interesting and lucrative medical finding. The speaker in this case was Eric Johnson, who was in the food research institute, and I think his appointment is also in bacteriology. He talked to us about the botullinum toxin. This is a bacterially produced material that is incredibly poisonous. I'll show you in a minute just how poisonous it is. He talked about the work of Edward Schantz who was just finishing he career when I came here in 1971. Here's Ed Schantz. Here's a table that shows you how poisonous botullinum toxin is. If you want to kill a mouse you give him a fraction of a nanogram of this stuff. 

A nanogram is-- if you took a thousand nanograms and put them in the palm of your hand you still wouldn't see it. So this is rather a small amount. If, by comparison, you wanted to kill a mouse with cyanide, which is pretty bad poison too, it would take 3 million times more cyanide to kill a mouse than this toxin. It's very poisonous. My acquaintance with this toxin came shortly after I came to Madison and one of my students was brought to trial for killing her boyfriend with cyanide. It turned out that she'd tried to get botullinum toxin but it was too well locked up on campus and she had to settle for cyanide. Schantz did the early work on this toxin. He purified it. He characterized its effectiveness in various assays. When he took it to WARF, the Wisconsin Alumni Research Foundation, to talk about patenting it. 

WARF decided not to. I suppose they didn't want to have a patent on the world's worst poison. It makes some sense. What they didn't appreciate was it became a very useful medical tool. The stuff we now call Botox is nothing more than what Ed Schantz purified 30 years ago. Used in very small quantities it can be injected under the skin and inactivate muscles that will relax and unwind-- What do you call them? >> Wrinkles. >> Wrinkles. Wrinkles, yeah, wrinkles. I was trying to repress that word. [laughter] So there was a long and interesting legal history here. 

It's not ended yet. But in any case, this was a chance to patent something really lucrative and it was passed up, I presume, because nobody wants to be in charge of poisons. Okay, I want to just turn for the last couple of minutes to another of the aspects of this course, which we can InterAg. It's taught not out of a department but out of the college of agriculture. It's InterAg 375. We have our Tuesday history lectures about which I've shown you a little. We have our Thursday lectures on modern research. I have said nothing about that, but those lectures were great too. I just don't have time. Then we have the Thursday session where we get some hands on experience with some of these things that were talked about on Tuesday and Thursday. 

Here, for example, is Stephen Babcock in the good, old days. What he's doing is a Babcock butterfat test. He's looking at exactly the same thing, exactly the same thing, that this guys is doing. We've got a old Babcock centrifuge. It looks like that. We found some of the old tubes. And it turned out that we were able easily to determine the butterfat content of stuff we bought in the supermarket. It worked like a charm. Paul Williams, who had told us a story about cabbage, invited the whole class, 20 year olds, who were in the class in the lab, to come a laboratory and make kimchee. Kimchee is fermented cabbage. 

He had brought every kind of vegetable you can imagine. Everybody made a different concoction. They all stuffed this stuff into old pop bottles. A week later they got together to celebrate the fact that their kimchee had actually fermented and it was good stuff. It had an interesting color and smell. This kid, the reason he's in motion is that this guy had used terrible red peppers in his. He'd rubbed his eye with it. The whole time that we were taking pictures he was in constant motion. [laughter] Here is laboratory that went along with the lecture on reproductive endocrinology, by Casida. George Shook from the Department of Fairy Science, animal science, got at the slaughter houses in Milwaukee, ten female reproductive tracts from cows. 

They brought them over to a room where the students were able to dissect them, and actually to experience artificial insemination vicariously. This is the device that is used for that purpose. The emphasis here was on the use of techniques that allow you to figure out exactly when a cow ovulates, so you know exactly when to inseminate. It was a very interesting discussion lead by people who really knew their stuff. It was good because of that. Then we went across to the dairy barn and watched a couple of professionals use ultrasound to look inside a cow to see whether she had ovulated. The subject was intensely interesting, shall we say. He is a guy, this is a graduate student in animal science, who is literally up to his shoulder in the back of a cow with the ultrasound probe in his hand, and the picture here. And sure enough, we could actually look at that TV screen and see whether the cow had ovulated. Everybody liked that. 

[laughter] Then the last option that we offered students was that, if they wished, they could choose an old instrument. I have quite a collection of old stuff. They could restore it to life, to function, and use it in an experiment that they would then write up. A number of students did that. Here are six cases in point. Here's an old analytical balance that somebody put back into working shape and wrote a wonderful operation manual for. Here's a Babcock centrifuge for determining butterfat content. This is the device that was used before spectrophotometers. It's called a colorimeter in which your eye is the detector. This is the first photometer to actually use electricity and photo tubes. 

This is a gadget that was plugged into the top of a microscope. When you looked through it you could see the spectrum of the tissue you where looking at. It was used to discover proteins called cytochromes. This is a wonderful collection of wedge-shaped devices that are cells that you can pass light through from left to right. As you lift the wedge-shaped thing up and down you're changing the length of the path that the light goes through. You change it until it matched another color. Then your eye has told you that this is the right stuff. These are all things that haven't suffered much from age because they're just optics. They're not electronics, or anything like that. The students did a great job of taking these things apart and putting them together. 

We do, as you heard, have one machine that's been orphaned up in the second floor of the biochemistry building. All of its component parts are spread over a whole bench. At the last part of the course we decided to try to summarize the themes that we had seen as we went through these several kinds of experiences. I'll end by showing you those themes. We were very surprised, I think, at how much politics was involved, and probably still is involved, in the agriculture school. In the early days it wasn't clear that the Ag school would be in Madison. In fact, it was to be someplace else. There was a hot competition for it. In those days Ag schools were usually constituted in a different place from the university. That's why we have Iowa and Iowa State, and Michigan and Michigan State, and so on. 

There was a political tangle here, but it was won by the people who wanted to have the Ag school here. That's probably a good thing that that happened. The second thing that's very clear, although maybe not from what I've told you tonight but from what we heard in the course, is that from the very beginning, the Ag school really did the right things to exemplify the Wisconsin Idea. When Henry was the first Dean he spent his whole first year circulating all over Wisconsin asking farmers, what do you need? What can we do for you? Then he came back and he said to Babcock, we need this. That's an application of the Wisconsin Idea, I'd say. The second Dean of the college, Russell, came in around the turn of he century or a little after it. He replaced Henry. He was determined to make of the college a real research center. He decided that he wanted people to do things that were good, sound, fundamental science. That has been a working principle ever since. 

It works. The scientific method applied to all kinds of problems, simple and complicated, has worked. I've already mentioned that a lot of what went on in the college in those years was interdisciplinary. It's still true to some extant. Wisconsin still had quite a reputation for being easy to work in across departmental lines. But we don't know each other as well as they did then. Because there are so many more of us, and we don't have time to talk to each other. It's a loss, I think. There are so, so many cases of solving a practical problem for a farmer that ended up to yield benefits, monetary of otherwise,  later. Studying feeds led to vitamins for humans. 

I haven't talked about Karl Paul Link and the Warfarin discovery, but that was discovered in an effort to help a farmer with a specific serious farm problem. I've talked about Botulism and Botox. In many cases, the stuff that started out as very practical agricultural problem eventually became highly relevant in human medicines. An early look at vitamins led to the cure for pellagra, anemia, rickets, goiters, the discovery of a very potent anticoagulant that saved many surgical patients from the clots that might otherwise have killed them. The disease phenylketonuria was studied here indirectly early on in the century and eventually revealed to be a defect in amino acid metabolism. Here's Henry Lardy's sperm parachute. It thought you should see that. [laughter] But the point of this is that research that started out as a practical pursuit very often ends up as having a very big economic effect. If you increase the yield of any crop on a farm by ten percent, that's millions and millions of dollars for the state. A small increment over the whole state has a huge effect. 

So all of these things made Wisconsin agriculture better and more competitive; the discovery of cold curing, which one of Babcock's other contributions, the preservation of sperm and artificial insemination, the work I told you about for cabbage wilt, the use of Warfarin as a rodenticide and as a blood thinner. All these things had big impacts on Wisconsin. I'm sure that is you worked out the economics that the return on investment was as good as you can ever get as an investment. One of the things that it's not easy to see in any one of these talks that we gave but sort of emerges if you look at all of them, is that quite often a field in science will move ahead for awhile and then stall out because you've reached a point where you need a technique and it doesn't exist. You need something more sensitive or you need something that provides a tool that you don't have. When somebody comes along and provides that tool there's a leap forward in science. The analytical balance was the tool of people of Babcock's generation. McCollum came along and revolutionized nutrition by saying, let's work on little animals and do it faster. Lederberg developed a technique called replica plating that allowed him to manipulate genes, and suddenly everybody was using it. Preservation of bull sperm. 

I haven't mentioned Truog, but he was a member Soil Science Department who figured out how to measure the acidity of soil for you could check your farm and see if it needed to be limed any place. That had a big impact on yield. So again and again you see these places where technical innovations, not just fundamental findings but technical innovations, have a big impact. We talked a lot about patenting. You know, of course, about WARF which takes the patentable things from the laboratories here and licences them, and makes a lot of money from them. There was a lot of disagreement over the years about whether patenting things like this was the right thing to do. Babcock said he didn't want to patent the Babcock test. He later regretted it very much because it turned out that by not patenting it he allowed other less ethical people to build knock-offs that didn't work. Then they discredited his method. When Steenbock came along with the process for making vitamin D he did patent it. 

They set up the Wisconsin Alumni Research Foundation. It has been a huge asset to the whole campus. The Botox story is one in which there might have been major income. Gobind Khorana, a Noble Prize winner, passed up a chance to patent one of the most lucrative biotechnology devices ever. The last thing I want to say is that these people were not talked about a lot. But the campus had people, has people, that really made a big splash in their scientific fields. Walker won the Wolf Prize. Bob Buris, I haven't spoken about him but he was a biochemist, he won the Wolf Prize. Lardy, Wolf Prize, First Wolf Prize. Four equivalents of the Nobel Prize in the College of Agriculture. 

There were, in fact, four Nobel Prizes in the basic sciences also awarded to people who were in one way or another attached to departments in the college. Here's Josh Lederberg, Gobind Khorana, Howard Temin. Temin was not in genetics but he did work that was very much genetic. And also Oliver Smithies. I guess the bottom line as far as I'm concerned is, looking at the history of this place, convinces me you have a lot to be proud of in your university. It's probably not a bad deal. I'd continue to pay taxes if I were you. [laughter and applause]