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cc >> Welcome, everyone, to Wednesday Nite at the Lab. I'm Tom Zinnen. I work here at the UW-Madison Biotech Center. I also work for UW-Extension Cooperative Extension, and on behalf of those folks and our other co-organizers, Wisconsin Public Television, the Wisconsin Alumni Association, and the UW-Madison Science Alliance, thanks again for coming to Wednesday Nite at the Lab. We do this every Wednesday night, 50 times a year. Tonight we're going to have a splendid story from one of our best storytellers. Dave Nelson is here to talk with us about Henry Lardy, his work, his research, his inventions, and the innovation that's called the Enzyme Institute. Universities do quite a few things to try to compete with other universities. One of them is to set up new research institutions, preferably early in the field's pioneering phase. And I think Dave's going to tell a great story not only of the Enzyme Institute but of a driving force and figure there with the story of Henry Lardy. I knew Henry Lardy by reputation as the person who invented the extender for bull semen and as the co-inventor of this. Now, I don't have any bull semen extended for you tonight.

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But this is one of the icons of molecular biology. This is what you see on TV when people are going to B roll or when they're doing the CSI series. To be able to do this is a remarkable thing. This is micropipetting, and this was co-invented by Henry Lardy. He invented an icon. He helped establish an industry. I think you're going to have a great story from Dave Nelson tonight. Dave was born in Fairmont, Minnesota. He went to college at St. Olaf. Then he went to Stanford for his PhD. He postdoced at Harvard. He came here in 1971. He is the co-author along with Dave Cox, his colleague in the Department of Biochemistry, of The Principles of Biochemistry textbook, which is the best selling biochemistry textbook in the United States. He's an extraordinary storyteller. I look forward to hearing what he has to tell us about Henry Lardy and the Enzyme Institute here at UW Madison. Please join me in welcoming Dave back to Wednesday Nite at the Lab.

APPLAUSE

>> Thanks, Tom, and welcome. The story that I'm going to tell you tonight has two heroes. One is Henry Lardy, a person whose work and whose personal qualities were heroic, and the other is a place, the Enzyme Institute, which Henry spent 50 or more years of his life. Unfortunately neither of them is still with us, but they have both left a lasting heritage that I want to tell you about to some extent tonight. These are two pictures of Henry about 55 years apart. Now, if I can find-- There we go. So, the story is actually rather torturous one. I hope you won't feel tortured.

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But it involves several people and several places that we need to look at before we can understand where the Enzyme Institute came from. The story begins, I think, with Conrad Elvehjem, whom many of you have heard of, of course. Elvehjem was a local boy. He grew up on a farm in McFarland. He got his PhD at the University of Wisconsin with EB Hart. He spent some time abroad, as almost all biochemists did then, with -- in the United Kingdom. Elvehjem had a distinguished career as a scientist and biochemist. He discovered, for example, the role of niacin in curing the serious human disease pellagra. He spent much of his scientific life studying the enzymology oxidation reactions, and so he was an enzymologist. He eventually was elected to the National Academy of Science. He was awarded the Lasker Award, usually the last step before the Nobel Prize. He was nominated several times for the Nobel Prize. He became chairman of the biochemistry department, then dean of the graduate school, then president of the UW at the time when we still had presidents, and he died literally in office. He died in the president's office. And Elvehjem's part of the story here is that he was actually the prime mover, or one of two prime movers that led eventually to the Enzyme Institute. The other one was Van Potter, who also may be very familiar to you. I've talked about him here before in other Wednesday Nites at the Lab. Van Potter was born on a farm in South Dakota. He was educated at South Dakota State College, which, it so happens, is where Henry Lardy was educated as well. He studied here to get his degree. Then he, as almost all American postdocs did, he went abroad, in his case to Sweden and to the United Kingdom, for a sort of polishing of for his doctoral work or his postdoctoral work. Then he became a member of the faculty here and was a distinguished member of the faculty for some 60 years. He too was elected to the National Academy of Science, and he too was an enzymologist of the first rank. He also wrote a book that was far ahead of his time. The book, Global Bioethics, in which he introduced the term bioethics and warned us 20 or 30 years before anybody else did that we were ruining our environment. I said that both Elvehjem and Potter had studied abroad in Europe, and that was very common. It was because, I think, for the first 20 or 30 years of the 20th century the European scientists were well ahead of American scientists in biochemistry, organic chemistry, and it made sense to go there to learn the most recent findings, to get the most recent techniques. The Europeans had a system that we hadn't here. For example, in Germany there was the Kaiser Wilhelm Institutes. One for physical chemistry, one for chemistry, one for physics. Each of these was a place very well funded, located usually in a central site in a major city, and occupied by one hero who ran the whole show and a large number of people around him, it was always him, who essentially served as assistants in the research program. These were very effective programs, and a lot of very important science came out of Germany and France at that period when these were at their apex, the period between the first and second wars. Here's a Kaiser Wilhelm Institute picture. You see the boss right here. Old guy. He was complete boss. When he said something, it got done. When he died, the place was dissolved and they started all over again. And the people around him were often people that had been with him for many years. Technicians often stayed for a lifetime with somebody like this. So it was a postdoctoral research institution, not a college, not a university. The people who were the boss of such places were invariably very distinguished scientists. Here's a list, for example, that includes Bothe, Debye, Haber, Hahn, Heisenberg, all physicists; Fischer, Warburg, Meyerhof, Kuhn, all biochemists or chemists. Every one of these heads of the Max Planck Institute, sorry, the Kaiser Wilhelm Institute were Nobel Prize winners. So they were extraordinary people, they were extraordinary places, and they accounted for the fact that Americans wanted to study abroad. For example, Otto Warburg, in the Max Planck, the Kaiser Wilhelm Institute in Germany, spent the first 30 years of the 20th century unraveling the process by which we digest our food, our sugars. He found, with much help from others, that the sugar glucose was broken down in 10 steps into something that yielded energy, and the energy was then used to do all the things that we need

to do

move, make new products, and so on. Warburg established that each of these 10 steps was caused to happen by a specific protein, a microscopic molecule like a tiny tool that was capable of turning something into something else. And each of these 10 steps represented a change of something into something else, catalyzed by an enzyme. The period of Warburg's preeminence in Europe was a period of enzymology, and the real effort was to pull apart individual enzymes, that's what they do in the laboratory in vitro, and then one hoped put together the whole pathway that they catalyzed so that we would, for example, understand exactly how glucose in the blood is used to make energy. Warburg's made a number of key observations. He learned how to separate enzymes, one from another. He discovered that there were such things as co-enzymes, molecules that helped enzymes and were, generally speaking, made from vitamins. In making that discovery, he made us understand why we need vitamins. They are co-factors. He recognized very early the role of certain specific chemical species, like iron ions. He made an observation, I think close to a hundred years ago, 70 years at least, that still stands and still remains unexplained, and that is that tumor tissues, for reasons we don't understand, use glucose at a very much higher rate and by a different pathway than normal cells. And this surely is a key to understanding cancer, but we haven't figured out how to open the lock. Warburg, there at the Kaiser Wilhelm Institute, was in the position with his technical staff, very expert technical staff, to build new instruments, like a spectrophotometer that allowed him to measure the absorption of light by various kinds of biochemicals. He developed and used beautifully a device called a Warburg respirometer, shown here on the right, which took advantage of the fact that in many biochemical transformations a gas is produced. So when we break down sugar with its six carbons, they are turned into carbon dioxide, a gas, and if you want to know how fast the sugar is being broken down by the enzymes, you just measure the rate at which carbon dioxide, the gas, is produced. This simple gadget traps the enzyme in a closed system, and when the gas is produced it pushes a device, a manometer, a distance that relates to how much gas was produced. Tremendously clever instrument. In the hands of an expert like Warburg, it made it possible to unravel a big part of the metabolic scheme that any textbook of biochemistry has now. Well, Elvehjem went to Europe to study as a postdoc, and while he was there he wrote this letter back to Hart, who was then the chairman of the biochemistry department here. This was 1930. I was glad to have your letter and to learn that there would be a job waiting for me when I returned. I can't say I'm exceedingly happy over the salary, but we can talk about that later.

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to do

But what I am wondering about now is if you will buy a Barcroft for me. Barcroft was another type of device, another manometer that measured gas changes. If we're going to continue to work on the minor inorganic elements, it will come in very handy. In fact, there are a thousand things to do in regard to the catalytic action of copper before leaving it in favor of the other elements. So he was writing back, saying please buy me one of these devices so I can bring it home with me. Apparently Hart did, Elvehjem brought it back, and we still have it. It's in my office. Beautiful device. It was used with terrific results in those times. Well, the business of going to Europe to be trained as a postdoc ended dramatically with the war. Here is a picture of the Kaiser Wilhelm Institute for Chemistry on the left before the war and on the right afterward. This happened all over Europe. The major research institutions to which Americans had gone to study were simply gone. And this caused Americans to think about what they might do to replace those opportunities for postdoctoral training. Here are three people who more than thought, they actually acted. King, Charles G King, was the co-discoverer of vitamin C. He, in 1945, right after the end of the war, wrote to Rockefeller Foundation, which is one of the few places where there was still money available after the war, suggesting that there should be some kind of American equivalent to the Kaiser Wilhelm Institute. At the very same time, Potter and Elvehjem, Potter is at the top, Elvehjem at the bottom, went to a meeting in Philadelphia. As they fell asleep at night sharing a room they chatted about the same problem of finding a place to actually train postdocs, and they got the idea together that the UW should actually try to develop one of these institutes here and that the institute should be dedicated to enzymology, which is of course Elvehjem's and Potter's specialty. And as you'll see, it was a major specialty of the campus. At that time, EB Fred, a bacteriologist, a scientist, was the president of the university, and of course he was receptive to this kind of suggestion, and it happened. The university decided, with the help of the Rockefeller Foundation, to build a new building and set up a new institute, the Institute for Enzyme Research. $100,000 from Rockefeller, $350,000 from WARF, which by then had begun to realize the profits from the patents on vitamin D and started to spend them on campus developments. And so they put together a building which was opened in 1949. You might wonder why the choice of enzymes of all the things that could have been studied in such a place, and why Wisconsin. And I think this is one answer. This is a list of the winners of the so-called Paul-Lewis Award, an international award for excellence in enzymology, and in the years 1946 to 1949, every year it was won by a Wisconsin biochemist. And '55 another Wisconsin biochemist. Then the name of the award was changed to Pfizer and some people won it. The place was a hotbed of enzymology. This is a copy of the draft of a memorandum that went to EB Fred from Elvehjem and Potter.

And here we read

With the loss of the great European centers for the postdoctorate training of research workers in the field of enzymology, the United States must develop one or more such centers in this country. At present no such center exists. There are many reasons why the University of Wisconsin might be developed into such a center. And in this memorandum, which I've truncated here, there were a variety of arguments given, but one of them was they pointed out that Madison is unusual in having both the medical school and the College of Agriculture, and also, of course, Letters and Science in the same town. That's not true of most universities. Michigan and Michigan States. Iowa, Iowa State. Texas, Texas A&M. Separated agriculture from the main campus. And it was here that the presence of agriculture provided an opportunity for enzymologists who studied animal enzymology that wasn't present every place else. There was also, they pointed out, a packing plant here. One of the remarkable stories of the packing plant, Oscar Mayer, is the story of the purification of a hormone out there which required 50,000 pig pineal glands. Pig pineal gland is the size of a pea. It's in the middle of your head. 50,000 were required for this. You can imagine the carnage that was involved in this biochemistry. But it turned out that the packing plant's presence was a huge asset. It turned out at the Enzyme Institute every morning somebody got in a station wagon, drove out to Oscar, picked up a whole bunch of pails of bovine hearts, heart muscle, brought them back to the Enzyme Institute, ground them up, separated the fractions of the cells, and by noon they had pails full of mitochondria that they could hand out to the members of the Enzyme Institute for their use. It was an amazing operation. There was also a brewery. And I think here they were referring probably to Pabst in Milwaukee. But it turns out that breweries, which grow tremendous concentrations of yeast, have all of the products that yeasts make, and some of those are very valuable to biochemists. They also pointed out that the campus, for a variety of reasons, had accumulated a collection of unusually good equipment that was available to do enzymology here too. So it was decided, and the building was built. Even before the building was finished, David Green was selected as the first director of one of the sections of the Enzyme Institute. The plan all along had been to have a place where there were multiple groups. Each a section unto itself. Each section organized, more or less, like the Kaiser Wilhelm Institute where the boss was boss. David Green was a famous young enzymologist. Born in New York, educated there. Got his PhD in Cambridge where he acquired a powerful English accent that lasted the rest of his life.

LAUGHTER

And here we read

He was for a while in the faculty at Columbia University, and as a young man was doing very promising enzymological studies of how fats were broken down. He accepted the chance to come here even before there was a building. He worked in sort of a Quonset hut on the property that now belongs to the athletic department, across the street from the Enzyme Institute. And in 1949 the institute opened. He was widely regarded as a comer. He had studied primarily things like the breakdown and the synthesis of fats and was there for right in the middle of the field of enzymology. A logical choice. Henry Lardy was the other choice. Born in South Dakota, Roslyn. Educated at South Dakota State like Van Potter. An amazing long career here, 1945 to 2010, during which he achieved virtually every honor that a scientist of biochemistry could aspire to. He was elected to the National Academy of Science before I was born. He won the Wolf Foundation Award in Agriculture which is generally considered the Nobel Prize in agriculture. And he had many honorary scrolls in his desk draws. Lardy started at South Dakota State, and I have to read you a little, if I can find it here. How I became a biochemist. Growing up in rural South Dakota during the combined plague of drought, dust storms, and economic depression tended to drive one's aspirations. There must be opportunities elsewhere that would provide an alternative life. The highest career goal to which I aspired was to become a high school teacher and in preparation I began college at South Dakota State (now University) in the autumn of 1935. Needing money for tuition and living costs, I sought part-time work in the Dairy Science Department assuming that my farm experience would qualify me for any possible opening. Well, he didn't end up teaching science in high school because it turns out he was very good in the laboratory. And in a very short time, as an undergraduate at South Dakota State, he did work that had lasting value. His first study there was a vitamin D deficiency in cows. We sometimes think that Wisconsin had the monopoly on vitamin D, but that was certainly not the case. Then he worked with a guy, Alvin Moxon, who actually trained six people at South Dakota State who became professors here. The question he took up there was the toxicity of selenium, which was rich in the soil of western South Dakota and which got into the plants, and the plants then were consumed by the cattle and they suffered selenium poisoning. Henry got involved in trying to understand what the poisoning was about and how he might deal with it. They used dogs in their experiments, and they deliberately had them eat foods that had selenium in them. Here is his account of the experiment that he did while an undergraduate there. I fed two dogs a diet containing 10 parts per million of selenium from West River corn, and in a few weeks they developed distended abdomens that could be tapped for a liter of ascites fluid every few days. They were retaining fluid in a big way. Then he had heard someplace that bromobenzene could react with selenium in the laboratory, and he thought it might do so in the animal, so he says, I gave each a capsule containing a gram of bromobenzene, and the next morning both dogs were slim as greyhounds and wading in urine.

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And here we read

It worked. There was no FDA that had to be cleared of these things.

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And here we read

And it turns out that bromobenzene is used. It was actually used to treat human patients who were poisoned by selenium. Amazing early demonstration of research acumen. During that period that he was at South Dakota State, Moxon, the mentor for these people, took six of his undergraduates, piled them in a little old car, drove from South Dakota to Madison because he wanted them to see the University of Wisconsin Madison. On the way they stopped briefly in Rochester at the Mayo Clinic, and they saw Kendall, who was to win the Nobel Prize for the discovery of hormones. And Kendall there was isolating steroid hormones from huge pots of tissues, just as I said took place here at Oscar. I think that experience of seeing Kendall and the steroid isolation actually registered on him and lasted his whole life because he came back to it again and again, and, as you'll see, he ended up his life studying steroids in humans and other animals. These six who came with Moxon all ended up coming to Madison. Five got PhDs here, one got a master's and went back to work, but it was an amazing group, and we'll hear more about them a bit later. So, when Henry got here, he came here as a graduate student, he joined the laboratory of Phillips, Paul Phillips, in the middle here. Here's Henry Lardy, a very young Henry Lardy. I don't recognize this person. Does anybody here know who that is by chance? Well, he'll go unnamed. But in any case, Paul Phillips was the mentor, and he turned out to be a marvelous mentor who produced not only the student Henry Lardy but a number of others who went on to very distinguished careers. When he worked in Paul Phillips' lab the first assignment he got was to try to deal with a problem that farmers were facing every day. By this time, dairy science had replaced wheat farming completely in Wisconsin. Farmers were all dairy farmers. They had to keep a bull to inseminate the cows, and the bull was by far the most dangerous part of the farm. So he was assigned the job, it was known by this time that you could actually artificially inseminate a cow by transferring semen from the bull to the cow. But it was also known that the semen was not stable. So you couldn't get very far with it before it was no good anymore. You couldn't use a prize bull on this farm to inseminate a cow on somebody else's farm or another county or another country. So the assignment was find some way that sperm can be made more stable for insemination. And this first-year graduate student was assigned this job. He was also assigned a bull whose name was Pabst Comet, which Lardy described as a vicious beast.

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And here we read

He said when the graduate students in the department heard that he'd been assigned Pabst Comet, it was as if he'd been promoted to first-string quarterback as a freshman.

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And here we read

The assignment was to find something not exotic, something available on the farm that would do the job. And it turns out that very quickly, in five months, Henry Lardy found that if he used egg yolk, fortified slightly with a buffer to keep the acidity it controlled, that would stabilize sperm long enough to do the job. He also showed very quickly that it worked for stallions and for rams and turkeys, and this opened up the possibility of a whole industry. Artificial insemination is by far the major way of inseminating animals of several kinds now, certainly of dairy cows, and it's a multi-billion-dollar industry. Partly because it supports the dairy industry, partly because this is a way you breed better cows. You have a prized bull, you can spread the semen around and have a better chance of getting more good cows. This is what happens if you're not careful when you're collecting sperm.

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And here we read

So you can see that it's a chancy business. The work that Henry did actually made possible the industry that ABS leads. When you go down route 90 now, north of Madison, you see ABS. They always have these clever signs. One of them says, "We deliver the male."

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And here we read

One of them says, "Our bulls never shoot blanks, happy hunting." But this turns out is a multi-billion-dollar industry. Here's a newspaper article from 1989 that describes the role of Henry and Paul Phillips. Here they are working the laboratory. Here's a picture, the people are not identified, but it's interesting because there's an airplane in the picture. You don't immediately associate airplanes with artificial insemination, but it turns out that they were used for this purpose because in those days the roads, the country roads in Wisconsin, got muddy in the spring, and they were not navigable. You couldn't drive a car over them. So they actually parachuted sperm...

LAUGHTER

And here we read

Onto farms. This is a real museum exhibit and it was really done. So the history here started before Henry when Casida first demonstrated that insemination artificially was possible, and there was a long series of developments in which the university hired and supported people who advanced this cause. But this work of Lardy and Phillips was the seminal work, if you'll forgive the...

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And here we read

And it resulted in the award 40 years later of the Wolf Prize in Agriculture to Henry Lardy. After him, Neal First picked up the project. And Neal went well beyond simple insemination to do in vitro fertilization, and he won the Wolf Prize for that work. And then Oliver Smithies carried on further with work that allowed the production of what we call knock-out mice, medical models in which you deliberately knock out a single gene in a mouse and ask now how is he. All those things were made possible by this early work. It's a remarkable achievement. And remember, we're talking about a first-year graduate student. So he did win this award, the Wolf Prize. Here is a picture of two people who won the prize. The other is his friend and colleague Bob Burris, also a graduate of South Dakota State, also who worked in the laboratory of Moxon on selenium. Something was, there was good chemistry there somehow. Well, back to Lardy's education. I've talked about his first graduate student year. When he finished his doctoral degree he went not to Europe but to Toronto to study with HOL Fischer who was himself a famous chemist but was the son of an extremely famous chemist, Emil Fisher. And there, Lardy learned about the chemical synthesis of sugars and sugar phosphates. He synthesized in the laboratory large quantities of glucose six phosphate, which is just then being found to be important in metabolism. And clearly that work in the Fischer laboratory was where he got his initial interest in the means by which we change one sugar into another. He came back here after his postdoctoral year, was appointed to the faculty, and for five years before he went to the Enzyme Institute, he worked in this building, the old biochemistry building straight across the street from us, where he did a variety of things, some of which were essentially assigned to him by the dean of the agriculture school. For example, at that time there was real concern about the transmission of DDT from crops onto which had been sprayed to the butterfat in dairy cows. And Lardy looked into this and measured quantitatively the carryover of DDT and made recommendations that were important. He continued his interest in the synthesis of rare sugars. On the side, on Saturday afternoons I guess, he worked with a student in Elvehjem's lab to establish the importance of biotin, the vitamins in the fixation of carbon dioxide. That's a major contribution. He studied a number of other enzyme catalyze reactions that also required vitamins, folic acid in the synthesis of serine, glycine, and the purines. What he said about this time, this first five years of a faculty member,

is

Our biochemical interests were catholic, and one's journal reading covered broader areas in the '40s than is possible now. And that's a gross understatement because it turns out that nobody in his right mind would attempt to keep his fingers in as many different pies as Henry Lardy did during these fives years, but he did so very successfully. He also continued to be interested in sperm. He used the respirometer that he brought back from Europe, here he is in front of it, to study the effects of thyroid hormone on sperm. The question was, is there an effect, and the answer was, yes. He looked at a compound called DNP that had been identified as a potential weight loss compound. It caused people who ate it to raise body temperature a little bit and to burn fuel that they weren't using efficiently. They dissipated the energy as heat. So it looked like a great way to burn up your fat without exercising. The only small difficulty was that DNP also killed you.

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is

Which ended its usefulness as a dietary. But his studies of this compound allowed him to make a very central observation about the way all individuals that live in oxygen atmospheres make their energy. And it turned out that his identification of DNP in this role was key in the subsequent many years later solution to the major problem of the 20th century in biology, how we make ATP. Here's another quote from Henry, looking back at the end of his career. "As a graduate student I shared authorship with members of five other departments besides biochemistry." He wasn't bragging here, but he was pointing out that in those days there was tremendous collaboration across departmental lines. The school was smaller. There were fewer people. There was less red tape, I'm sure. But it's striking when you look at those papers from that period at how many times people from three or four or five departments would gang up on a problem and solve it. Lardy was actually very interested in designing equipment, and one of the things that he designed was the device shown here that was intended to save work or save drudgery for the person using this respirometer that I mentioned before. It used to be when these things were introduced, the experimenter would deal with one, then move his chair down, deal with another one, move his chair down. I guess this got old after a while. And so Lardy actually put these things on a Lazy Susan so he sat still and the Lazy Susan brought the respirometers to him. And characteristically he didn't just build it for himself, but he actually wrote up the design, published it, worked together with Gilson from Middleton, who was a faculty member in the medical school, to build a prototype, and here it is. This is sitting on the desk in my laboratory. This was the first one they built, and it's currently under appraisal for reconstitution. There's a brave student in the history of science who wants to see if he can make this work again. This instrument development was of serious interest of Henry. And as Tom pointed out earlier, the pipettor, the automatic pipettor, which every biochemist lives with now, came out of this same collaboration with Gilson, Warren Gilson. He is now gone, but his son runs Gilson, a large firm now in Middleton, an international firm. Well, after five years in biochemistry, Lardy was ready to be selected for the role of section head at the Enzyme Institute, and he accepted that with some trepidation. He had some concerns about working with David Green. But in the correspondence that we have seen between them and among several people concerned here, they clearly had worked a modus operandi. And here they are. Here's Henry Lardy. Here's David Green. Here's Conrad Elvehjem. And they're standing in front of the old Enzyme Institute thinking to themselves, I wonder how this is going to work out.

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is

Elvehjem probably praying that this would work out. Because by this time, Green, who had only been here for about six months, had already established a reputation for being pretty rigid and for wanting to do things strictly his way. And he'd already gotten himself into a little bit of hot water with the administration. Well, the rest of the story I can't begin to tell in detail, and it would require talking about chemistry too much tonight anyway, but I want to give you some idea of the breadth of his research interests. This is terribly unusual. Most people choose a single subject and spend 40 or 50 years of their life studying. He, in his career, studied and made important contributions on the biology of sperm and fertilization, I've said he worked out the function of a vitamin, biotin, he did very interesting work with thyroid hormones which still is relevant to human medicine, he made very important contributions to understanding how we make our central fuel, ATP, and his observation about the role of DNP was part of the reason he was able to make this contribution. When we breathe hard, our mitochondria, where ATP is made, get busy and go. And when we're relaxing, they slow down. And it's always been interesting to understand how that is accomplished. Very central regulatory process in humans. And Lardy published a paper in which he very clearly identified the means by which respiration is controlled. He became interested in carbohydrate metabolism and especially in the synthesis of glucose from scratch, so-called gluconeogenesis. He studied the enzymes of gluconeogenesis. He became interested in the possibility that defects in one or more of these enzymes might be the factor that contributes to sudden infant death syndrome. He got interested in thyroid hormone, and through it, into the effective thyroid hormone on temperature control, and through that, an interest in obesity and cold adaptation. And he published a long series of papers, edited a book on this subject. And then, amazingly, after a career of this many different important contributions, he changed directions completely when he retired at 65 and developed a whole new area of research that he spent his next 25 years on. This was on his desk when Henry left us. It's the start of a manuscript. This is his writing. The name of the manuscript is Electron Transfer Roots, Metabolic Efficiency, and Thermal Regulation. But the interesting thing about this manuscript is the first line. "Sixty-two years ago, one of us found that the oxidation of the ketone bodies..." and so on. Now, how many biochemists can ever say that? Sixty-two years ago most biochemists weren't born. And this emphasizes, I hope, the extraordinary length of his career. In that career he trained about 60 graduate students, about a hundred postdocs. I didn't say so but the operating principle at the Enzyme Institute was to focus on postdocs. He published well over 500 papers, and these recent studies that I'll tell you about briefly of hormones, steroid hormones, were described in a number of papers. When he retired, about the time he retired, the Enzyme Institute space got crowded. And here he is looking back at that time. When he retired there was not enough space to carry out the kinds of studies I had done before, so I turned to steroids. I knew next to nothing about steroids. This is a 65-year-old man talking about what he's planning to do with his life. But newspapers had been carrying stories about a new compound that seemed to have magical properties, DHEA. It is the most abundant steroid in humans and made in the adrenal glands. And its role is actually very poorly understood. It's amazing to me that somebody hadn't paid much more attention to this sooner. But he did pay attention. This is the only slide I'm showing you that's not mine. It's his. It's the slide he used to introduce his interest in DHEA, which is a picture of the structure and of the several things that he first thought it might be involved in. And he means the biochemical community had reason to think that each of these things might be related to DHEA. And so he set up a laboratory with new sets of equipment, new techniques, new people, new directions, and for 25 years he studied the metabolism of this hormone, DHEA, and looked at its effects on the whole set of physiological parameters that I just showed you there. That is worth another whole long talk, and I can't give it to you tonight. Now I want to just talk about some personal things about Henry Lardy that I found that I was deeply impressed with, let's say. One of the things I discovered in going through his papers was that there were several cases in which something had been written by somebody, Hal Derbauer, and had been cribbed by Henry Lardy. The same poem with a few changes was there with his name on it. I knew that wasn't possible. I knew he would never do that. It was totally out of character for him. And I wondered what the hell was going on here. I just couldn't imagine it. Until after looking at several of the things, it finally dawned on me that Hal Derbauer was Henry A Lardy, the farmer. It was his pen name. And he wrote short stories and poems under that pen name. In his spare time, he bred animals, both retrievers and stallions. And right alongside the folders in his desk drawer about gluconeogenesis and sudden infant death syndrome, there are the stallions and the retrievers. He was a great outdoorsman. I think some of you in the audience may recognize yourself in some of these pictures now. This is a bunch of his cronies from the faulty shooting bunnies. Is the two of, by any chance?

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is

Yeah, well, in any case, he was out there. And here you are in the picture. One of the things that continually amazed me about Henry and made a lot us admire him in a way that we admire very few scientists, he managed somehow, in spite of investing a tremendous amount of effort and energy and time in his science, to be a good man. To be a family man. To care about things that really mattered. And for people, young assistant professors struggling to try to get a career started, it was a real inspiration to see that it was possible, barely possible if you were good, to do this and still have a life. He had long term friendships that he maintained. He sent out Christmas letters every year to the whole gang that he had. Here's a picture to remind us. Here's one of his old friends. Here's Lawrence Anderson over here as a graduate student, and here he is 60 years later with Henry. They're still both enjoying each other's friendships. He had a number of long-term and very close friendships, and the correspondence between these friends are fascinating. One of those friends was Paul Boyer, who came here the same time Henry started, started graduate school at the same time. They had a lot in common and spent a lot of time together and spent their rest of their lives, actually, working in very similar directions. Paul Boyer was primarily interested in how we make ATP. Henry Lardy spent a lot of his life asking the same question. And they retained that common interest in their friendship. Now I want to spend just a couple of minutes to say a bit about the Enzyme Institute. I said it was the other hero of the story, and I'll finish this story in just a few minutes. Helmut Beinert, a German biochemist who was displaced by the Second World War, ended up in an Air Force base in Texas, found his way somehow to Madison, and got a job with David Green in the Enzyme Institute where he immediately showed himself to be unusual in the good sense. He was a very outstanding scientist. Eventually he became the direction of section three of the Enzyme Institute, which by then had actually grown in size. There was more space. He studied a variety of topics that were spin-offs from what David Green had studied, and he introduced into biochemistry a couple of techniques. One, electron paramagnetic resonance, that allowed him to look at a class of proteins that nobody else could. And he quickly became the world's master of that science. Gobind Khorana was a chemist, an organic chemist from India, actually from Punjab, who was at a Canadian west coast university, I've forgotten which one it was, when Van Potter recognized his potential affinity for the research that was going on here. He was making compounds that people here were interested in having. Van Potter spearheaded the effort to get Khorana to come here. He came, he became a director of the Enzyme Institute, was here for many years. He was interested in making from scratch in the laboratory the molecules that we now know to be the stuff of genes. And he was, in fact, the first one to have synthesized in the laboratory from scratch a functional gene for which he won the Nobel Prize. This is a picture of Henry and Gobind. It must have been five or six years ago. There was a symposium in Gobind's honor. It was the last time he was here and probably the last time that these two saw each other. This is Masayasu Nomura, a member of the Enzyme Institute who came here as a part-time member of the genetics faculty. And his interests, like the rest of the people at the Enzyme Institute, was proteins. The protein machine that he was interested in was the ribosome that makes other proteins, which is composed of some 50 different proteins. And he had a crew, a huge crew of postdocs at the Enzyme Institute that separated these 50 proteins, one from another, got them pure in 50 different test tubes, and then learned how to recombine them so as to have the ribosome reconstituted from scratch. An amazing tour de force that Nomura carried out. And finally Mo Cleland, an enzymologist of the first class, who spent his life trying to understand how enzymes did what they did by measuring how fast they did what they did and what affected the speed at which they do it. Mo became the world's expert in the kinetic studies, and people came here from all over the world to work with him. Mo left us in 2013, and in fact by that time the whole group that we've talked about were gone. The Enzyme Institute was opened in 1947, and in 1999, for reasons that still are not clear to me, the university decided to close down the Enzyme Institute. They didn't actually chase everybody out of there. They grandfathered the people who still were there, and finally in 2012 the last of them retired. But the Enzyme Institute then had a run of about 50 years. Van Potter, who had been the driving force behind it, died in 2001. Elvehjem, of course, had died younger. He was younger. He died earlier. Green died in '83, and then in the one decade, Lardy, Beinert, Khorana, Nomura, and Mo Cleland all left us. And the Enzyme Institute was done. The university's way of accomplishing this was to ask that the remaining members of the Enzyme Institute be fused into the biochemistry department, but that basically meant the end of it. And it was a sad ending to me. I always wondered what was behind that, and some day I intend to try to investigate and understand what it was. But the loss of that hero raises these questions for me. One, whether postdoctoral training like this at an institute is even desirable. Universities like this one, predoctoral students, postdoctoral people, undergraduates all work together in a laboratory. They profit from each other's experience. The older help the younger and so on. But, inevitably, there's some drag. When you work with people who are not experienced, they are going to slow things down. And if you wanted to constitute a laboratory for the purpose of getting the answer as fast as possible, you probably wouldn't include undergraduates. So the second question is, if you want to have a place like this, which is sort of an elitist organization where you only worry about the most advanced students, should such an institute be separated from the university? What's required to establish and maintain such an institute? It isn't clear what caused ours to end, so it's not clear what it took to keep it going, but I think this deserves to be looked at carefully in the context of other institutes like this of which there are only a few. Where should the money come from? Should it come from the state? Should it come from private foundations as it did for many of these places? Not clear. And I think the biggest question that comes to my mind as I look at the history of the Enzyme Institute and the tremendous people who were there is whether this kind of a place can be actually created by will, deciding you're going to make a great center, or whether it only happens when you have people who are superb and have good luck to get a collection of people who are superb all at the same time. I don't know. I don't know, but I think somebody should investigate the history of the Enzyme Institute and write a history of it. It's a fascinating episode of the American science education. Thank you.

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