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Dr. Julius Axelrod Oral History 2003 C
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Interview with Dr. Julius Axelrod
Conducted on November 25, 2003,
by Dr. Marshall Nirenberg and Dr. Bernhard Witkop
Introduction: This is an oral history interview sponsored by the Office of NIH History on November 25, with Dr. Julius Axelrod (JA), now an emeritus scientist at the National Institutes of Health and formerly the Chief of the Section on Pharmacology in the National Institute of Mental Health. Dr. Axelrod won the 1970 Nobel Prize in Physiology or Medicine for his work on neurotransmitters. The interviewers are Dr. Marshall Nirenberg (MN), Chief of the Laboratory of Biochemical Genetics in the National Heart, Lung, and Blood Institute and also an intramural Nobel laureate, and Dr. Bernhard Witkop (BW), now an institute scholar and formerly the Chief of the Laboratory of Chemistry in the National Institute of Diabetes, Digestive and Kidney Disease.
BW: Julie, tell us about your parents and early upbringing.
JA: Well, my parents came to America from Eastern Europe around the beginning of this century. It was a great immigration of many Jews, called the Goldina Medina, the Golden Heaven, and they met here, they settled on the Lower East Side of New York. That was where most of the Jewish immigrants came and settled, on the Lower East Side. They met, and they came from a similar area in Eastern Poland, Galicia. They met here and married. And I was born in a tenement–in the fifth floor of a tenement on the Lower East Side, on East Houston Street, and my upbringing was very typical of immigrant Jews. I went to haida, as well as the public school, and I went to an elementary school which was built during the Civil War. It was very old, and one of the very distinguished graduates of this public school was Isidor Rabi (1898-1988).
Well, my life was mainly on the streets of the Lower East Side. We used to play all kinds of games, such as stick ball. I learned how to swim by jumping into the East River, which was very close to where I lived. I went to a junior high school, Mangin Junior High School, and when I graduated, I wanted to go to Stuyvesant High School. That was a high school, a very elitist high school for the very bright kids, but I wasn't good enough to get in, and I went to a school called the Seward Park High School. It was opposite, I remember, the Forward Building, that was the Yiddish newspaper at that time, and many of the graduates were very well-known entertainers, Zero Mostel, Tony Curtis—his name was Bernard Schwartz then—Walter Matthau.
You know, every dream of a Jewish mother is to have a son who is a doctor, and this was my goal, you know. I was very much influenced by my mother. She was a very wonderful lady, sweet. And when I graduated from high school, I saved up some money, and I was accepted by New York University. At that time, New York University had two parts; one on Greenwich Village, Washington Square, and one uptown. It was sort of a campus. I wanted to go to the uptown campus, because it was very much like, a lot like, a real college campus. I was interviewed by Admissions, and he asked me where I lived. I said I lived on East Houston [pronounced Howston] Street. "Oh," he said, "you mean Houston [pronounced Hyooston]," and I knew I wasn't going to be accepted.
I was accepted, though, at the Washington Square annex of New York University. The reason I went to New York University, I thought it would give me a better chance to get into medical school. After a year, my money ran out, and I applied to City College. City College at that time was a tuition-free school, and it really had a Gothic campus, although it was in Harlem. I remember going from the tenements, the Lower East Side tenements, by subway to this Gothic campus, City College. It was really, I think, one of the most important influences in my life, going to City College. Most of the students were very bright and highly motivated, highly political. This was in 1930. It was the beginning of the Great Depression. As a premed, I majored in biology and chemistry, although my subjects I was most interested in were history and philosophy and literature.
I didn't do too badly in all of these courses, and I had some really wonderful professors. One of the professors was a very distinguished philosopher, Morris Rafael Cohen, and I was very much interested in philosophy. At City College there was a lot of turbulence at that time, you know, because of the rise of Hitler and anti-Semitism and fascism in Italy, Mussolini. City College, in a basement [of the main building] called Shepherd Hall, had various alcoves. Each alcove had a group of students which had different political ideas, and there were very many heated discussions amongst them. There were Trotskyites, the Stalinists, the Socialists. There were some fascist Italians there. I was just fascinated by this type of environment.
I graduated, and when I graduated, I applied to several medical schools. I wasn't accepted by any. I was very lucky; I heard that there were positions called volunteers, and I was interviewed by a very eminent biologist, William H. Park (1863-1939). He was the one who introduced diphtheria vaccine in this country. He suggested that I see a biochemist who had a laboratory at New York University Medical School. That was located then, and still is, on Thirtieth Street at First Avenue. I forget the name of the area.
K.G. Falk was the man who hired me. I was paid twenty-five dollars a month, but I was very, very glad to work in a laboratory. At the same time, I took an examination for a clerk in a post office. I was accepted, but I decided to work in a laboratory. You know, I had many decisions to make in my life, and, looking back, I made all the right ones, choosing the laboratory, although I could have gotten much more money working in the post office. Falk was working on enzymes in malignant tumors. He was supported by Harriman. It was called the Harriman Research Institute, which was located at New York University, and I assisted him in working on enzymes, esterhydrolyzing enzymes in malignant tumors.
Falk wrote a book in 1924. He studied biochemistry in Europe. He was very much influenced by a very famous biochemist, Richard Willstatter (1872-1942), who believed enzymes were just catalysts which were adsorbed on proteins. He believed it till the day he died, even after J.B. Sumner (1887-1955, Nobel Prize 1946) crystallized urease. Well, anyway, it was an interesting job. It was not great research, but I had a little taste of research. I worked there for two years, and I decided to get married. I met a lovely lady, Sally Taub, who ultimately became a schoolteacher. I knew I couldn't get married on $25 a month. Even in those times, $25 a month wasn't very much.
Fortunately, vitamins were then discovered and introduced and used as supplements. They were added to milk and pills and things. The City of New York set up a laboratory to establish whether the supplements, the vitamin supplements that they added to milk and things, were what they said on the label. And they set up a laboratory to see, and I was hired. It was called the Laboratory of Industrial Hygiene. I was hired, and I was given a good enough salary to get married. The experience I got at this laboratory was to test vitamins in foods, and this involved reading the literature and applying the methods that were published in the literature of foods, and it was very good experience for me. They also had the Journal of Biological Chemistry, which I used to read, and I became very much interested in the developments in those days. One interesting development was the discovery of dicoumarol. I happen to know the man who made this discovery. It was Karl Link.
BW: Karl Paul Link (1901-1978).
JA: Right. He looked like a Shakespearean actor. He had a cape and a black broad-rimmed hat. I followed the story. Cows were dying of sweet clover disease, and they bled to death. Link was a professor at Madison, Wisconsin, and I happened to read each installment of the isolation of the active principle, while I was working at the Laboratory of Industrial Hygiene, on the vitamin. He isolated the active principle of sweet clover disease, dicoumarol. He went to the clinicians at Wisconsin and suggested perhaps it would be a good anticoagulant. They looked him up and down. "You're just a farmer," they said. "You'll kill people," they said. "It's rat poison."
However, there were very astute clinicians at the Mayo Clinic, which wasn't very far, and they introduced—well, this is one of the side issues. I used to read the Journal of Biological Chemistry regularly, and I became very much interested in research, although I was doing this fairly routine thing, although it involved some type of ingenuity, you know, to apply a method, say Vitamin A, to test it in foods. Also they had assays, bioassays, for Vitamin D, for example. What we did is, we used a diet which was free of Vitamin D, and the rats came down with rickets. How we tested it, we'd take the bone and use a silver stain, etc. I remember, while I was working, I had to make up the diets for these. I used to go to the Fleishman Yeast laboratories in the Bronx. I always liked going there, because it was opposite Yankee Stadium, and I took the opportunity to go to the ball game while I was there.
The experience, at least in retrospect, was very useful. I'll get to how I got into research in a minute. The head of the laboratory was a very distinguished pharmacologist, George B. Wallace, who was a former professor, head of the Department of Pharmacology at New York University, and he actually was the editor of the Journal of Pharmacology and Experimental Therapeutics. One day a group of manufacturers of analgesics, called the Institute of the Study of Analgesic Drugs, came to Wallace with a problem, because some of the non-aspirin analgesics used in those days were acetanilide and phenacetin, and one of the problems was that some people became habituated to these. They had them in Alka Seltzer, whatever, and some of them came down with methemoglobinemia. They were very concerned and wanted to know why.
They came to Wallace for advice, and Wallace asked me if I would like to work on this problem. I said, "I have never had any research experience." "Well, I suggest you see a colleague of mine, a former colleague, Bernard Brodie." Do you want me to go on, or do you have another . . .
MN: Sure. This is exciting.
JA: [Laughs] I was asked to talk. Well, I went to see Brodie, Dr. Brodie, in his office. At that time, it was Goldwater Memorial Hospital, which was on one of the islands on the East River.
BW: Welfare Island, yes.
JA: You know Goldwater. We'll come to that. I went to visit him. I remember the day. It was February 12th. It was Columbus Day, I think, in 1946—to discuss this problem with him, and he told me something which I vaguely was aware of. He told me that anytime one takes any kind of a chemical, a drug, it's transformed in the body. One thing I learned from Brodie is to ask the right questions, and he asked me to put the structure of acetanilide on the board, on his blackboard, and he looked at it for a while. I don't know whether you can visualize acetylanilide. It's a benzene ring having an amino group which was acetylated, and one of the transformation products could be a de-acetylation to aniline.
I looked up the literature and saw that an aniline could cause methemoglobinemia. If you ask the right question, you have to go about learning how to answer these questions. The next thing, I developed a method—one thing I was good at it—developed a method to measure aniline, and how it was done is to diazotization and couple it to a dye so it would have a color. I developed a method, with Brodie's help, a very sensitive one. I took some acetylanilide—I found some aniline in my urine, and this, of course, was one of the most exhilarating experiences—you would know this, Marshall—when you make an important discovery for the first time.
MN: It's exciting.
JA: There's nothing like it. And we found that if we give aniline to dogs, it causes methemoglobinemia.
BW: And what about the metabolite? You found the metabolite.
JA: Oh, yes. That was even more important. [Laughs] I don't know. You have so many other questions, but starting with your first question . . .
BW: You were on the threshold of becoming a millionaire.
JA: Well, at that time, I was working for a University and couldn't patent things. But anyway, the aniline represented only 4 percent of the ingested acetanilide, and that was completely metabolized, in a rabbit, anyway. So we wondered—Brodie and I interacted. He was a very stimulating, charismatic man, and he really fired you up, you know. We suspected that one of the metabolites would result from a hydroxylation on a para-position. We developed a method for it, and we found it was in the urine and most of the blood, N-acetyl-para-amino phenol. We had it tested for its analgesic activity. It was analgesic, just as good as the original parent compound, and it represented about 80 percent of the metabolites, and it was nontoxic.
When we published our first paper, we said that should be considered as a safe analgesic. It doesn't cause methemoglobinemia. And it's what is known today as Tylenol. Actually, if you write "N-acetyl-para-amino phenol," Tylenol is encrypted in that. The same thing, acetaminophen is also. Anyway, that was my first experience in research. I loved it, and I thought, "This is what I wanted to do for the rest of my life."
MN: That's terrific.
JA: And, you know, Goldwater was a very unusual place. I was struck lucky, you know. I'd like to digress, give a little background about Goldwater. During the war, the Japanese cut off the supply of quinine, and the troops were fighting in the Pacific, and they needed desperately an anti-malarial. So they set up a unit at Goldwater headed by James Shannon (1904-1994). James Shannon was a professor of physiology at NYU, worked on the kidney secretions, etc., but he happened to be, ultimately, one of the great scientific leaders, you know, administrators. Well, he was the head of that program to test drug levels, to test whether synthetic drugs were anti-malarial drugs. It was a very stimulating atmosphere that I was thrown into. Although it was after the war, they continued working, and they had some very, very bright people there. Many of them came here to the NIH. There was Robert Berliner (1915-2002).
MN: Berliner was there?
JA: There was Zubrod in cancer. There was Bowman, Bob Bowman; Sid Udenfriend; Herb Weissbach. Well, anyway, let's go on. If you have any other questions we can—that's my beginning.
BW: Yes. You're attaching the memories. You know, we both arrived at the same time, in 1950. You came from Goldwater. We came from Harvard. We were a small minority of only four or five people, among them, the later Nobel laureate Chris Anfinsen (1916-1995) and Earl Stadtman, of course. And then when we met for the first time, I think you were part of the retinue of Sidney Udenfriend (1918-1999), and immediately you sent out good vibes. I wrote recently, with your help, the biographical memoir of Sidney Udenfriend, who died four years ago as the director of the Roche Institute of Molecular Biology, one of the few cases where somebody left the "NIH rest home" to go into the cruel world in order to compete, and he did very well. And I think you will remember the stimuli that you got from Udenfriend.
I may go back to what Vicky Harden said. She said the first Paul Ehrlich Lecture, which was established in 1988, when I retired, demonstrated quite clearly how scientific ideas are connected over time and how an understanding of what has gone before may lead to fruitful new research. I think the environment and the closeness of Udenfriend, his interest in serotonin, guided your research into many directions, so that you laid the fundament for the treatment of depression. Can you tell us about it?
JA: Yes. Well, I'll come to that later. That comes later, but let me continue this story. I'd like to do it chronologically, because it's an interesting story. I just had a bachelor's degree. Brodie had his lab. Shannon persuaded Brodie to come to the NIH. At that time, Congress had established the various institutes, you know, Mental Health and the Heart Institute, Arthritis, etc., and I was in the Heart Institute. The Heart Institute was located in Building Three, and also the Arthritis Institute. That Building Three was really one of the great—it's a small building, three-story building, but it's one of the most fertile grounds for research.
In that building, there were five future Nobel laureates. There was Chris Anfinsen; (Nobel Prize 1972) there was Arthur Kornberg (Nobel Prize 1959); and there was Stan Prusiner (Nobel Prize 1997), who was a postdoc with Earl Stadtman; and Michael Brown (Nobel Prize 1985). Chris was a postdoc also. All from that one building. Imagine. More than half of them became members of the National Academy. It was a terrific—I don't know whether you remember this building, Building Three.
MN: Oh, I remember it. Absolutely.
JA: Yes. Also, Leon Heppel was there. Well, anyway, and that was the building I was assigned to, and there was nothing like being around such great scientists, future scientists. You know, it was a wonderful experience for me. And we all worked freely–we knew what we were doing. We exchanged ideas. It was nothing like today, you know. It's such an enormous institution.
BW: Did you join Shannon's poker club?
JA: Oh, yes. Well, yes. That was Udenfriend's. It was called "Applied Statistics." We had put up a notice that on Friday we were going to have a meeting of "Applied Statistics." That was the poker club. You know, we used to play poker. [Laughter] Anyway, I remember Shirley Udenfriend used to have a special table for it.
MN: Tell me about your studies on ephedrine, caffeine, and amphetamine.
JA: Yes. When I was working for Brodie, I was working in a big team, and I didn't like it, and I was offered a job, I think, with Smith Kline. I told him I'd got it, and he says, "Well, what will it do for you to stay?" I say, "Well, I want independence." He said, "Okay." And so one of the problems, I became very much interested in a group of compounds called sympathomimetic amines. These compounds were synthesized in 1912 by Barger and Dale. I don't know whether you know Sir Henry Dale (1875-1968, Nobel Prize 1936). He was a famous British pharmacologist in 1912.
Brodie's lab concentrated on metabolism of drugs, and that was one of the things I became pretty good at. One of the drugs I was very much interested in was ephedrine. Ephedrine had an interesting history. It was part of the Chinese pharmacopeia. It was used for 5,000 years. It was called, the active ingredient, Ma Huang. In the 1930s, it was Schmidt and Chen—I think it's Chen—isolated the active principal and showed the structure of ephedrine. It was ephedrine. And they found that if you give it to humans, it elevates blood pressure. Now there are big problems about it. But anyway, I worked on the metabolism of ephedrine. I felt it was metabolized by various hydroxylations, demethylation, methylation, conjugation and also amphetamine.
Amphetamine was actually introduced by Gordon Alles. I forget where he was. And, of course, it was a stimulant. Students used it a lot, you know, and truck drivers who want to stay awake. And also one of the interesting effects of amphetamine was that if you give enough of it, it'll cause the symptoms of paranoia, almost like schizophrenia. And I was very much interested in these drugs. Another drug I studied was caffeine. They knew nothing about the metabolism of caffeine. It was the most widely used drug, you know. I studied that.
This became the kind of work I did. This was in the early 1950s. One thing that struck me is that why are these drugs, which the body has never seen, transformed, changed, by different routes? For example, amphetamine is hydroxylated. Ephedrine was demethylated, etcetera. Like many other biochemists and pharmacologists, I became very much interested in how the body could do this. Fortunately, I had, who shared my laboratory, a postdoc named Gordy Tompkins. He was brilliant, and he kept me in stitches. He was funny. He was a wonderful guy.
MN: Charismatic. Charismatic. Funny person, yes.
JA: Actually influenced you a lot, didn't he?
MN: He certainly did. He gave me my first job, actually.
JA: He did?
MN: Yes. But go ahead.
JA: Well, you know the kind of guy he is. [Laughs] I discussed it with him. He says, "Why don't you find out what enzyme..." I said, "Well, I never had any experience in enzymology." He says, "Well," he says, "all you'll need is a liver and a razor blade and some Krebs Ringer's solution. You have a method for amphetamine?" I said, "Yes," "Okay. Become an enzymologist. It was a very daring, bold idea, to find why the body can metabolize these drugs, because a lot of people have tried for a hundred years. Well, anyway, it was just as well I was so naïve, the kind of experiments I did.
Well, the first thing I did was use a liver slice—it was a rabbit—and added amphetamine. It was completely metabolized. And I found that what happened was it was deaminated, and it wasn't the monoamine oxidase that did it; it was a totally new enzyme. Of course, I became very much taken with enzymology, though. And at that time it was Schneider and Hogeboom, I think, devised methods for separating the various subcellular fractions by using isotonic sucrose, and differential centrifugation. You remember that, definitely.
BW: Yes.
JA: Well, anyway, I wanted to find out in which subcellular fraction this was taking place, and when I separated mitochondria, the [homogenized] endoplasmic retuculum particulates which we call the microsomes, and the cytosol. When I added amphetamine, none of them [the subcellular fractions] metabolized it. But when I added a cytosol together with the microsomes and added all kinds of co-factors, it was metabolized. And I found that it was TPN, and the microsomes and the cytosol that can metabolize amphetamine. And so the problem was, where was the enzyme located, the cytosol or the microsome? One is supplying something to the other.
So what I did was heat it to 55 degrees. When I heated the cytosol to 55 degrees and added the microsome and TPN, it worked; it deaminated. [amphetamine]. But when I heated the microsomes and added the cytosol, it didn't anymore. So I knew the enzyme was in the microsomes. And what is the cytosol doing, and what is the TPN doing? Well, one thing about Building Three, you knew what everybody else was doing. And I went to Bernard Horecker, who was working on a pentose phosphate pathway, and that required TPN. I asked him if he'd give me some of the substrates for that, and he gave me three. I think it was phosphogluconate and isocitrlic acid, and glucose-6-phosphate. But when I added—one thing, I was a little sloppy. I didn't wash the microsome, so there was a little cytosol and when I added it to the microsomes, added it to the washed microsomes, it deaminated amphetamine. And the common thing about these three substrates is that TPN was reduced, it also required oxygen.
I also found the enzyme that demethylated ephedrine. When I added ephedrine to the same system, it reduced TPN and microsomes, it was demethylated, so I knew that it was a new enzyme. And, actually, I remember there was no such thing as Sigma then, where you could buy it. You had to make the TPNH yourself. And Gordy Tompkins helped me make the TPNH–you know, reducing it. And then, there it was. Well, there's one thing. Brodie was very upset I didn't tell him about this, why I didn't tell him, because I know if I told him it was his problem. But I don't want to go into that. But anyway . . .
MN: You were working on your own, though?
JA: Sure. Yes.
BW: Under the wings of Brodie. [Laughs]
JA: But I didn't tell him what I was doing, because I knew if I did, it wouldn't be my problem anymore. But anyway, well, this was, I think, one of the best things I've ever done. Now it is called the cytochrome p450 enzyme. It's a big thing, you know. It's just that, you know, I did it on my own. I was the solo author, and I realized that I really could work on my own.
MN: But wasn't the next step norepinephrine, how that is metabolized?
JA: Oh, that's later. Yes. Well, anyway, I want the next question.
MN: Well, I mean, you discovered the system, the microsomal drug metabolizing enzymes.
JA: Yes. Well, this is how I did it.
BW: That's fantastic.
JA: Of course, I'm not giving you the impression that every experiment I did worked, you know. Most experiments, you know, don't work. You have to try one thing and another. But you don't want to hear all that, boring failed experiments. But anyway . . .
MN: What compelled you to get a Ph.D.?
JA: I can tell you what compelled me. I asked for a promotion. I was a GS-11 then. I discovered this group of enzymes, the metabolism of all of this. I thought I deserved it. But, you know, the bureaucracy said if you didn't have a Ph.D.—you can't get a GS-12 without a Ph.D. Well, anyway, I said, "To hell with that. I'm going to leave." I happened to know a professor George Mandel at G.W. [George Washington University]. I asked him if I could take a Ph.D. I got a master's while I worked in New York, in chemistry. Well, fortunately, in order to get a Ph.D. at G.W., you have to take certain required courses which I already took for my master's. You have to take five exams, all-day exams, and write a dissertation.
He says, "As far as the dissertation, you can use—." I told him about the microsomal enzymes, so I didn't have to really—I'd published twenty-five papers already at that time. "And take those exams," which I did. They were really tough. And I got a Ph.D. I became very much interested in working with amphetamine, with drugs that affect the mind. I applied to the Mental Health Institute, and Seymour Kety (1915-2000) interviewed me. Evidently, I really wanted to work with Giulio Cantoni. Fortunately, Kety advised me, "No, you'd better work with somebody else."
Anyway, Ed Evarts (1926-1985) came over to my lab. He knew my work on amphetamines, and he knew I was looking for a position. He was at Mental Health–I sent my CV around. He said, "How would you like to work in my lab?" He was the head of the lab of clinical science. I said, "I'd love to." He was such a wonderful person. He let me alone. He said, "You don't have to work on schizophrenia. Do whatever you want, as long as it's novel and important." He gave me complete freedom to work, and this is how I came to the NIMH in 1955. It was wonderful. I was glad I changed, and I'm glad I changed the direction of my research. I became very much interested in the chemistry of psychoactive drugs.
The first problem I worked on was the metabolism of LSD, and LSD, at that time in psychiatry was very fashionable. They thought this would give you the clue to schizophrenia, but LSD has—a very astute nurse, psychiatric nurse, can tell the difference between anybody who took LSD and amphetamine, because LSD doesn't resemble schizophrenia at all, but amphetamine does. But anyway, they were very much interested in LSD and so we worked on the metabolism, and I collaborated. First, developed a method. Bob Bowman, who used to work at Goldwater, was then building a model fluorophotometer, spectrophotometer. It was a collaboration with Sid Udenfriend, and I used his experimental models, which ultimately became the Aminco-Bowman, which was very important in neurotransmitter research for serotonin.
BW: It's in the Stetten Museum, you know, a classical instrument. DeWitt Stetten, Jr., (1909-1990) was instrumental in collecting classical instruments, and the Bowman-Aminco spectrofluorimeter is on exhibit here in the museum.
JA: Oh, is it?
MN: You haven't seen it?
JA: Yes, of course. It was in Building Ten. That's right. Bowman's an interesting guy, you know.
BW: Bowman's a genius. He's a genius.
JA: He's a physician, you know, but he liked to tinker. You know, when he was at Goldwater, he developed the flamephotometer to measure sodium.
BW: Really?
JA: Sodium in the blood, you know. Sodium is very important, the electrolytes, you know, with all kinds of diseases. Well, it was Bowman who built the flame photometer. He liked to do all tinkering, and he built this Aminco-Bowman spectrophotometer. Also, Sid was very much interested, Sid Udenfriend. He wrote a book on the spectrophotoflurometer in medicine. You remember that?
BW: Oh, very much so, yes. It has a Volume One and a Volume Two.
JA: Yes. Well, anyway, Bernhard and I collaborated on the LSD problem.
BW: Yes, and I had, at that time, relations with the discoverer of LSD, whose name is Albert Hoffmann. He was a research leader at Sandoz, and he described his exposure to LSD, which is active in micrograms. I think the normal dose of LSD that sends you into the beyond is about twenty-five micrograms, and the question was, how can you study the metabolism of something that is active at twenty-five micrograms? And probably, if you give much higher doses, they are lethal. So it was Julie's idea to use microsomes, and that did it.
I have the description of Hoffmann, who actually made the compound in '38, but he didn't get wise to the effect. But on April 16, '43, he weighed out some new LSD, and he made LSD, which is the lysergic acid diethylamide, because choramine, the nicotinic amide diethylamide, is a cardiac stimulant, you know. And he thought if choramine is active, then lysergic acid with a diethylamino group may also be active, and he didn't realize how active until he weighed it out and inhaled traces of it, and he said . . .
JA: Don't they put it on the tongue or something?
BW: Yes. No, he weighed it out, and then he said, "I was forced to interrupt my work in the laboratory in the middle of the afternoon and proceed home, being affected by a remarkable restlessness combined with a slight dizziness. At home, I lay down and sank into a not-unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed, I found the daylight to be unpleasantly glaring. I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense kaleidoscopic play of colors. After some two hours, this condition faded away."
And apparently, this experience became known, and he wrote a book, which he dedicated to me, LSD: My Problem Child. And this way, he came into contact with Aldous Huxley, (1894-1963) who, by the way, last week, when we deplored the assassination of President Kennedy, that was the day when Aldous Huxley died, and he died—you know, he had cancer—with the help—he wanted to do that—of about 100 micrograms of LSD. So the transition from time to eternity was very pleasant, according to witnessing of his wife. But now, the LSD story is yours.
JA: Well, he wrote a book called Doors of Perception. Do you remember?
BW: That was his book.
JA: Well, you know, it's interesting, just at that time, I was giving a talk on my work at the New York Academy, and Huxley came in, and he tripped over the projector where my slides were. [Laughter] Well, anyway, it's an interesting story, you know, how LSD, Timothy Leary and all that . . .
BW: Gordon Wasson extended it, then, to—I mean, you were interested in mescaline first.
JA: Yes.
4BW: And Evarts worked with you, I worked with you, on mescaline, and then you extended it to LSD.
JA: Yes. Well, this is my introduction to mental health, you know.
MN: It's a great introduction.
JA: It was very colorful, but it really had no medicinal value. You know, many physicians used it. I think some actors–Cary Grant or something, used some of that stuff.
MN: Why did you start to study glucuronides?
JA: Well, that was another interesting story. I was just leaving the Heart Institute. I was going for my Ph.D. And I bumped into Jack Strominger, and I mentioned a paper by Dutton and Storey, two Scotch biochemists, who showed that in order to form a glucuronide, you need the cofactor uridine diphosphate glucuronic acid, UDPGA. "You know," he says, "I'll bet I know how that's made. It's made from uridine diphosphate glucose." He says, "Yes, and I have a method to measure glucuronide, because I found an enzyme—it showed how morphine formed a glucuronide." "But where can we get some UDPG?" He says, "Well, you know, Herman Kalckar (1908-1991) is here, and he has some. Let's bring him into the problem."
And actually, I remember I did that experiment. I had a week before I had to go for my Ph.D., and I said, "this procedure requires uridine diphosphate glucuronic acid, a liver, and is it TPN or DPN?" We found that it was DPN. Its the color of morphine, you could see that. I remember that. And I left the problem, because I had to go to get my Ph.D. But Strominger had purified the enzyme, worked with Kalckar, etcetera. But the interesting part of glucuronide was, you know, Rudi Schmid was here, and he showed that jaundice was caused by bilirubin and how bilirubin was detoxified to prevent jaundice to form bilirubin glucuronide. He identified it.
I says, "Well, I'll bet I know the enzyme that can make it, because we have the cofactor." Jack Strominger and I just synthesized it, UDPGA." And so we added bilirubin and UDPGA in the liver. We found that it required TPN then. Well, anyway, so Castle at Harvard has a mutant strain of rats called a Gunn rat, which had jaundice. He said, "Well, we'd like to get some of those rats." And we found that the reason it had jaundice is they were very deficient in this glucuronide-forming enzyme. They couldn't detoxify bilirubin. That's another interesting clinical spinoff, you know, to some of the basic work.
MN: What made you change the direction of your research to go into psychoactive drugs?
JA: Well, it wasn't psychoactive drugs, it was mental health, but the reason I changed the direction of my research. I was very much interested in neurotransmitters. They had a very romantic history. I don't know whether you know this story. It was way back in 1904 that a student, whose name was Eliot—it wasn't T. S. Eliot. It was just Eliot—who was working for a very famous physiologist by the name of–it begins with an L. I can't remember it today. You know, my mind's going [J. N. Langley].
BW: You mean Sir Henry Dale?
JA: No. That's later on. It was–well, we'll call him L. [ J. N. Langley. (1834-1906)]. Anyway, he was the one that described the sympathetic nerves, a very famous—but Eliot was a student of this guy. And Eliot found that—adrenaline was just isolated by a guy [John Jacob Abel (1857-1938)] from [Johns] Hopkins [University].
BW: Dale?
JA: No. Well, anyway, he [John Jacob Abel] isolated the active principle of the adrenal medulla elevated as adrenaline, isolated adrenaline, epinephrine, from the adrenal medulla. When Eliot injected adrenaline to a dog, they responded as if the sympathetic nerves were stimulated, and he proposed that perhaps nerves act by liberating a chemical, like adrenaline, a chemical–there was a big argument, you know. At that time, the dogma was electrical transmission, you know.
BW: They had the dry school of pharmacology and the wet school of pharmacology.
JA: The wet and the dry. Well, anyway, in the abstract–he gave a paper at the British Physiology Society making his proposal, but his professor, he didn't believe in theories. He told him, "Forget about it. Don't mention it in the paper." And he actually didn't. But it struck the minds of a couple of investigators, particularly Otto Loewi (1873-1961, Nobel Prize 1936), who was a pharmacologist at Graz in Austria, who thought about this and said one day in a dream he dreamt of the experiment that proved chemical transmission. When he got up, he wrote it down on a pad, but Bernhard said maybe it was toilet paper. He couldn't read what he wrote. [Laughs]
JA: But anyway, he dreamt the same dream again, and he dashed to the laboratory with it, just an elegant experiment. What he did, he took two frog hearts. One was connected to the vegus nerve. He stimulated the vegus nerve, isolated frog heart in a bath, and it slowed the beat. He took the fluid and added it to another beaker, to a frog which didn't have the nerve, and that also slowed the beat. So he knew it was some chemical.
BW: Terrific experiment.
JA: Yes. Beautiful experiment. And it was Henry Dale who identified it as acetylcholine. Well that's one of the reasons that it has a fascinating history. And also it was interesting, you know, the psychological effects, and also clinically it was very important later on.
MN: How did you discover catechol-o- methyltransferase?
JA: Well, let's see now. Oh yes. Again, I got the abstracts of the Federation proceedings, the ones they used to hold at Atlantic City. I mean there's one here in Washington next year. I came across an abstract by Armstrong and McMillan, who found out that people have pheochromocytoma, which is a tumor of the adrenal gland. They excreted a lot of vamylmandelic acid, which is a catechol, which has a methyl group on a metaposition [of a catechol].
But anyway, that gave me an idea that perhaps epinephrine may be o-methylated because here was a tumor, an adrenal tumor, secretes a lot of adrenaline and here was this increase of an o-methylated product in the urine, so I suspected this may be one of the pathways for catechol metabolism by methylation. It was Cantoni who discovered
s-adenosylmethionine, and I didn't want to ask him for any—I didn't think he'd give me any. But anyway, I knew it required ATP, methionine and magnesium, so I put that all together and I found a metabolite–a new metabolite when I did paper chromatography and I suspected it was o-methylated epinephrine, so I called up Bernhard, said, "Will you synthesize this?"
BW: And this is the scheme that convinced Stockholm that here is an achievement that deserves the prize.
JA: Well, anyway, so we had the pathway of the adrenaline, and of course we purified the enzyme—I became a pretty good enzymologist by then. I isolated catechol-o-methyltranferase and found that not only adrenaline, but dopamine and L-dopa, any catechol will be methylated. After that, maybe a year or two after Don Brown—you know Don Brown?
JA: He had a lab. He was a postdoc of Marion Kies. I was telling him about these methyl enzymes, and he was interested in histamine metabolism. He said, "Let's make some C-14 methyl-S-adenosylmethionine enzymatically." We did it in a couple of days. That means anytime you add the C-14 labeled S-adenosylmethionine, the product will become radioactive. We discovered a couple of enzymes protein-carboxy-methylations. One of the nice things about NIH, you know, you could collaborate with people right away. I know it helped you a lot.
MN: I had some wonderful collaborations.
JA: Yes, you know Maxine Singer made the nucleotides for you, yes.
MN: Oh, absolutely. Absolutely.
BW: But Julie was in the shadow of Brodie. It was very hard to find out that you were the one who found out what reserpine does.
JA: Well, no, I didn't, really. No. I don't want to claim credit—it was actually Parkhurst Shore. I don't know if you remember him.
MN: I remember him.
JA: Parkhurst Shore had a discussion with Herb Weissbach, he suspected it was serotonin at that time, and Herb and Sid were working on metabolism of serotonin and said "Why don't you look for hydroxyindoleacetic acid in urine after you give reserpine," and he found, when he gave reserpine, a big elevation [in hydroxyindolacetic acid] and they knew it was depleting serotonin.
BW: And then they found out that Herb Weissbach had so much of this metabolizete of serotonin in his urine, that they wondered and found out the reason, because he ate two bananas in the morning, and bananas are full of serotonin, and this got Udenfriend into contact with United Fruit. He got an invitation from United Fruit.
JA: Maybe it should be an antidepressant, because you know how it works, it elevates serotonin. To hell with Prozac, eat bananas. [Laughs]
BW: You discovered the reuptake of norepiniphrine, didn't you?
JA: Yes. Well, yes. To follow, I'll get to that in a minute. We found metanephrine and all the metabolites with Bernhard's help. We'd get collaboration. Well, anyway, what happened, we found an inhibitor for catechol methyltransferase. It's been shown by this Swiss guy who worked on MAO—what's his name? Starts with a K [may be Keller]. He found an inhibitor for MAO. He found that it didn't inactivate epinephrine. You know who I mean.
BW: Yes. May be Alfred Pletscher of Roche?
JA: But he was someplace here. But anyway, when MAO was inhibited and COMT was inhibited, and you would inject adrenaline, noradrenaline. Usually when you inject it, it raises the blood pressure and goes down very fast because of these two enzymes. However, when we knocked out those two enzymes, inhibited them, and we injected norepinephrine, the blood pressure still went way down [rapidly]. Something was inactivating the effects of norepinephrine and it wasn't those two enzymes, because they weren't working. They were inhibited.
So, well, what do you do? It was something new. Well, one of the things I did when I worked with Brodie, I studied the distribution of drugs, where it went, and at that time Kety became head of the laboratory. Evarts stepped down. He didn't want to be the director of the Mental Health anymore; he stepped down. Kety gave a very interesting seminar describing the work of two Canadian psychiatrists, Hoffer and Osmond, saying when they let adrenaline stay out in the air, it turned pink, formed adronichrome, and when they—they took it themselves. They said they hallucinated. I was fascinated by this. Hallucinated. And they proposed that hallucination is caused by an abnormal metabolism of epinephrine adrenaline, because of adrenochrome.
So I spent four frustrating months trying to look for the enzyme that could convert adrenaline to adrenochrome and I could never find it. It was a lot of crap. But anyway, Kety wanted to test this hypothesis. He ordered some tritium labeled adrenaline because I already, with Bernhard's help, worked out all of the metabolites, the whole pathway of noradrenaline and dopamine. He wanted to see if those who have abnormal metabolism of adrenalin were schizophrenics—we had a ward with schizophrenics that get tests anyway. Well, anyway, I asked asked him for some. I wanted to do a distribution of adrenaline and noradrenaline because doing the endogenous [compound] is very difficult. So we injected radioactive adrenaline into a cat, and generally, you know, epinephrine was very rapidly metabolized, but what we found is that after two hours, there's a lot of adrenaline still in tissues, almost as much as after 2 minutes—and we suspected that somehow it was sequestered someplace.
I had a very good visiting scientist, a real good pharmacologist, George Hertting from Vienna, came for a couple of years to my lab, and we had big discussions. Why did it [epinephrine] stay around? Where is it going? And we found that generally it was highest in tissues like the heart and the spleen, that were heavily inervated by sympathetic nerves–these are noradrenaline containing–and we suspected it may be going into these nerves so how do you prove it? Hertting had a brilliant idea. You know, when you remove the ganglia, the superior cervical ganglia, pluck it out at one side, all of the nerves on that side disappear; they'd disintegrate. So you had a cat which had nerves intact on one side and absent on the other side. When we injected radioactive noradrenaline, all the radioactivity was on the inervated side. So we knew that it was going back into the sympathetic nerves.
Another experiment, what Hertting did is infused radioactive noradrenaline into the splenetic artery. It was a very complicated preparation which I could never do, having to avoid any artifacts.... So we stimulated the, I think the splenetic, nerve–it released the radioactive noradrenaline, so it was taken up and released. The whole process, it was a very novel phenomena, you know. That was 1959. But what we did then to see how would drugs affect reuptake, so what we did, one of our first experiments we did is give cocaine and then inject radioactive noradrenaline. We found the tissues such as the spleen, all the radioactivity was way down when you gave cocaine, because it blocked reuptake. And the same thing with amphetamine. But we wanted to know what happened in the brain, so Jacques Glowinsky, who was a postdoc, he found a way to introduce radioactive noradrenaline in the brain, in the lateral ventricle. So what we did, at that time the antidepressant drugs we used were imipramine, desipramine, amitriptyline.
So we got some from one of the drug companies, a whole series of tricyclics, some of which were clinically active in depression and some which were not. So while we introduced--injected--these drugs and then gave radioactive noradrenaline, all the clinically active tricyclics lowered the noradrenaline in the brain, so it blocked the reuptake, the phenomenon of reuptake. And later on, of course, they showed this could block serotonin and dopamine, this is how Prozac and Zoloft and Paxil were developed, saved the drug companies millions of dollars. Instead of testing them on humans, they can test them on rat brains and tell where there was going to be a potential, at least, of antidepressant, before they could test it. They saved a lot of money that way.
MN: It opened up a whole field of research.
JA: Very rapid development, a rapid introduction of antidepressant drugs, you know. Prozac, Paxil, and Zoloft and all of that. Yes, that was, again showing how basic work translated to a clinical... and make drug companies a lot of money, too. Particularly this Medicare bill they're going to pass today will make the drug companies a hell of a lot of money.
BW: Another candidate for the biochemical basis for schizophrenia was 6-hydroxydopamine, and Hans Thoenin at your lab found out how it works.
JA: He found out—no, that's an interesting story. Hans Thoenin, he as working for Hoffmann LaRoche in Switzerland. He was working sort of a very, very boring kind of work he was doing. He wanted to spend a year in my lab. I said, "You can come if you can bring 6-hydroxydopamine." What he found, that 6-hydroxydopamine, it was in Berne or something. Well, anyway, when he gave 6-hydroxydopamine, it destroyed catecholamine nerves. I said, "Bring that with you."
So what we did, we gave 6-hydroxydopamine to a rat. We found that tyrosine hydroxylase levels went way up. What 6-hydroxydopamine did is stimulate–this is the adrenal gland–it stimulates the sympathetic nerves. It stimulates the enzyme that makes dopamine and noradrenaline, goes up, and that's what we found.
BW: The 6-hydroxydopamine was first made by Hans Thoenin. And then John Daly got interested in it.
JA: He didn't know what it did, though.
MN: Well, I think it was Sjoerdsma at that time who worked with Udenfriend, and he gave it to dogs and he said, "Don't give me that stuff. It ruins my dogs." [Laughter] So we didn't research this any further.
JA: Well, anyway, yes, okay. Let's go on.
MN: Tell us about your work with Herb Weissbach on the biosynthesis of melatonin. That's an interesting thing.
JA: That was an interesting story, too. I occupied many–after I won a prize on . . . I came across a paper by Aaron Lerner at Yale, a very good biochemist as well as dermatologist, and he found that if you add [bovine] pineal extract to tadpoles, it will blanch the skin. Aaron thought that maybe—what is the active principle of the blanching? He isolated the active principle that he identified as melatonin, which is serotonin with a methyl group on it. I saw that paper. I was fascinated of course because I was working on methylation reaction.
And Herb Weissbach was working on the metabolism of serotonin at that time, so I had lunch–over here at the cafeteria where you meet people, you exchange ideas. We'd talk, and we had an idea, let's see if we can find the enzyme that makes melatonin by using radioactive S-adpnosylmethionine with serotonin. We found the enzyme. It was a pineal. It was highly localized in the pineal. So we found that enzyme, and not only that, it led to some other very interesting findings. It was discovered there was a serotonin rhythm in the pineal gland. It was low at daytime, high at night.
MN: Circadian rhythm.
JA: Solomon Snyder was then a postdoc of mine in the lab, and we didn't have a method for melatonin. Let's see whether this rhythm is a self-generating rhythm, a circadian rhythm." So we developed a method for serotonin [a precursor of melatonin], and we found that this rhythm of serotonin, if you cut the nerves to the brain, it will stop, this rhythm, so we knew there was a signal coming from the brain for this rhythm, serotonin.
There was actually at that time just—what's his name again? Bob Moore. He was then at San Diego, I think. He found the suprachiasmatic nucleus was the biological clock in the brain, that causes not only the melatonin rhythm, but also a lot of other rhythms. It's a big thing, you know, circadian. You have many genes involved in this biological clock. I don't know whether you're familiar. But anyway, one thing about working with the pineal gland, you know, almost all experiments worked. Every time I came depressed with working on other problems, I worked with the pineal, I always got a successful result. It lifted my spirits, my personal antidepressant. [Laughs]
Anyway, I found it fascinating. Recently they found how light can affect the serotonin rhythm. It has to come from the outside, you know, to affect this rhythm. Also one of the things we did with Solomon Snyder is when we kept in the complete darkness, the serotonin rhythm still persisted, so there was an endogenous clock. It was found later on the same thing with melatonin. And they found just two years ago, right across the street at the Naval Medical School, they found an opsin, a new opsin, melanopsin. Have you heard of it? Melanopsin. Actually, light reaches to the pineal through melanopsin without the rods and cones.
MN: That's fascinating. It really is. One of the most impressive things that I found is that over much of your career you've worked in the lab yourself and done your own experiments.
BW: How did that work? How many people did you work with?
JA: Oh, well, altogether I never had more than three or four postdocs, but I had a long career with about sixty people. I had visiting scientists and postdocs. I think I learn more from them, as much from them, as they learn from me. I think this interaction—I'm sure you all have had that experience.
MN: Absolutely.
JA: Working with bright people, you just trigger ideas, you know, talking and experiments, what kind of experiments are critical, and all of that. Are we being taped now?
MN: Yes.
JA: Yes, I find that I'm sure so many people came out of your lab, particularly, Gilman and that fellow from Harvard.
MN: Phil Leder, yes—wonderful people to work with.
JA: One thing about—you know, I don't think I could have done what I've done anyplace else but here. I was given complete freedom and just marvelous resources, both physical resources and intellectual resources. Nothing like it here.
BW: But Julie, in his modesty, was asked in '69 and he said, "Well, I have been at the Institute of Mental Health for five years, and I haven't done a thing for mental health." That was the year after, when, he got the Nobel Prize. [Laughs]
MN: I think that the basic findings that you made in neurochemistry are fantastic, and they've led to many things that are clinically used these days.
JA: I think the greatest satisfaction that I have, aside from making these basic discoveries, that it had clinical implication in pain and depression. This, I think, is the most satisfying thing I've had.
MN: Most of the current medicines that are used for depression came from your basic findings.
JA: Yes. But I think people don't understand the value of basic research and what it leads to. I think that passage you just showed me of Arthur Kornberg is a good example.
BW: When they closed the Roche Institute of Molecular Biology, I told Herb Weissbach, well, basic research is so important and nobody has formulated it better than Arthur Kornberg, who got his Nobel Prize as early as 1959, and he said, "The difficulty with research support in our society, I have come to realize, is the failure to understand the nature and importance of basic research. This failure can be seen among members of the lay public, political leaders, physicians, and even scientists themselves. Most people are not prepared for the time scale of basic research and the need for a critical mass of collective effort. Fragments of knowledge unwelcomed and unexploited are lost as were Gregor Mendel's genetic discoveries.
"The vast majority of legislators and some scientific directors cannot accept the seeming irrelevance of basic research. Were there a record of research grants in the Stone Age, it would likely show that major grants were awarded for proposals to build better stone axes, and that critics of the time ridiculed a tiny grant to someone fooling around with bronze and iron. People do not realize that when it comes to arguing their case for more funding, scientists who do the basic research are the least articulate, least organized, and least temperamentally equipped to justify what they are doing. In society, where selling is so important, where the medium is the message, these handicaps can spell extinction."
JA: Again, just this conversation we had, this example of how basic research led to discoveries that helped people, you know, over their afflictions. I think it's a pity that the funding for the NIH has been so drastically reduced. I think it's a shame. It will show, I think, with future discoveries.
MN: Do you have any advice to young scientists?
JA: Well, there's a German expression about research. It's "glück, geduld und geld."
MN: Three Gs. That's Paul Ehrlich.
JA: Well, yes. I think there are so many ways that one can do science. Depends on your temperament, your style, and you don't need a great brain or have all A's in your subjects. You have to have an imagination; you have to ask the right questions; you have to have a mentor that can inspire you. I would recommend, if you have the talent and the capacity to do it, it's a great life. I think we can all attest to this.
MN: I can second that.
JA: Thank you.
MN: Well, thank you very much.
[End of interview]
Alles, Gordon................................................................................................................................ 14
Anfinsen, Chris........................................................................................................................ 11, 12
Axelrod, Julius
And chemistry of psychoactive drugs.................................................................................... 19
And his first experience in research...................................................................................... 8, 9
And interest in neurotransmitters........................................................................................... 25
And studies on amphetamine......................................................................... 13, 15, 16, 19, 20
And studies on caffeine................................................................................................... 13, 14
And studies on ephedrine....................................................................................................... 13
And work on was the metabolism of LSD........................................................... 20, 21, 23, 24
As Chief of the Section on Pharmacology, NIMH.................................................................. 1
At Harriman Research Institute................................................................................................ 4
at Laboratory of Industrial Hygiene......................................................................................... 6
Early work at NIH............................................................................................................ 11‑13
Early years of life..................................................................................................................... 2
Earns Master's in chemistry.................................................................................................... 18
Earns Ph.D.............................................................................................................................. 18
Educational background................................................................................................. 2‑4, 18
Family background............................................................................................................... 1, 2
Feelings about NIH................................................................................................................ 38
Influence of City College......................................................................................................... 3
Joins NIMH in 1955............................................................................................................... 19
On meeting Sally Taub............................................................................................................. 5
Bowman, Bob.................................................................................................................... 10, 20, 21
British Physiology Society............................................................................................................. 27
Brodie, Bernard......................................................................................... 7‑9, 11, 13, 17, 27, 29‑32
Brown, Don................................................................................................................................... 28
Brown, Michael............................................................................................................................. 12
Cantoni, Giulio.............................................................................................................................. 19
Cohen, Morris Rafael....................................................................................................................... 3
Dale, Sir Henry........................................................................................................................ 13, 26
Evarts, Edward........................................................................................................................ 19, 24
Falk, K.G......................................................................................................................................... 4
Fleishman Yeast Laboratories.......................................................................................................... 6
George Washington University..................................................................................................... 18
Goldwater Memorial Hospital....................................................................................... 7, 10, 20, 21
Harden, Vicky............................................................................................................................... 11
Harriman Research Institute............................................................................................................ 4
Harvard University............................................................................................................ 10, 25, 38
Hoffman LaRoche (Switzerland).................................................................................................. 34
Hoffmann, Albert.................................................................................................................... 21, 22
Horecker, Bernard......................................................................................................................... 16
Huxley, Aldous.............................................................................................................................. 23
Institute of the Study of Analgesic Drugs...................................................................................... 7
Johns Hopkins University.............................................................................................................. 26
Journal of Biological Chemistry...................................................................................................... 6
Journal of Pharmacology and Experimental Therapeutics........................................................... 6, 7
Kalckar, Herman............................................................................................................................ 24
Kennedy, John F............................................................................................................................ 23
Kety, Seymour................................................................................................................... 19, 31, 32
Kies, Marion.................................................................................................................................. 29
Kornberg, Arthur..................................................................................................................... 12, 39
Laboratory of Industrial Hygiene................................................................................................ 5, 6
Lerner, Aaron................................................................................................................................. 35
Glowinsky, Jacques....................................................................................................................... 33
Link, Karl Paul............................................................................................................................. 5, 6
Loewi, Otto................................................................................................................................... 27
Mayo Clinic..................................................................................................................................... 6
McMillan, Armstrong.................................................................................................................... 28
Moore, Robert................................................................................................................................ 36
National Institute of Mental Health.............................................................................. 1, 19, 31, 38
National Institutes of Health......................................................................................... 1, 10, 11, 29
New York University......................................................................................................... 2‑4, 6, 10
Park, William H............................................................................................................................... 4
Prusiner, Stan................................................................................................................................. 12
Roche Institute of Molecular Biology..................................................................................... 11, 39
Schmid, Rudy................................................................................................................................ 25
Shannon, James........................................................................................................................ 10‑12
Shore, Parkhurst....................................................................................................................... 29, 30
Snyder, Solomon..................................................................................................................... 36, 37
Stadtman, Earl......................................................................................................................... 11, 12
Stetten Museum............................................................................................................................. 20
Strominger, Jack...................................................................................................................... 24, 25
Taub, Sally....................................................................................................................................... 5
Tompkins, Gordy..................................................................................................................... 14, 17
Thoemin, Hans......................................................................................................................... 34, 35
Udenfriend, Sidney.......................................................................................... 10‑12, 20, 21, 30, 35
United Fruit................................................................................................................................... 30
Wallace, George B....................................................................................................................... 6, 7
Wasson, Gordon............................................................................................................................ 23
Weissbach, Herb..................................................................................................... 10,30, 35, 36, 39
Willstatter, Richard.......................................................................................................................... 4
Witkop, Bernhard.................................................................................................21, 27, 28, 30........
Yale University.............................................................................................................................. 35
Yankee Stadium.............................................................................................................................. 6
Zubrod, Gordon..............................................................................................................................10
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Japanese 3D map data provider Dynamic Map Platform is acquiring American 3D map maker Ushr for $200 million. Both the firms currently deal in providing high-definition road maps in Japan and North America, respectively. For this acquisition, Dynamic Map Platform will raise about 22 billion yen ($198.9 million) from investors including two existing shareholders, the Japanese state-backed INCJ fund and Mitsubishi Electric.
Mitsubishi Electric Corporation has already announced that it will make an investment of about JPY 2 billion ($18 million) in the company. Ushr's current investors include GM Ventures, EnerTech Capital, Emerald Technology Ventures and Forte Ventures. Terms of the agreement are not being disclosed.
Using survey-grade LiDAR and camera technology, Ushr has mapped all controlled access highways in the United States and Canada; road features are represented in the map to within approximately four inches of geospatial accuracy. When combined with vehicles equipped with sensors and software enabling autonomous driving, Ushr's HD maps allow self-driving cars to safely operate on mapped roadways, providing precise lane centering, smooth control through curves and the ability to anticipate roadway changes. Ushr's market leading HD map technology was integrated into General Motors' Super Cruise, the industry's first true hands-free advanced driver assistance system for the highway, and first-to-market in the 2018 Cadillac CT6.


text:
BlackBerry PlayBook and EVO View 4G to be phased out at Sprint
Dan Graziano @dangraziano
Sprint has updated the company's end-of-life list to include two of its tablets. Shipments of the carrier's BlackBerry Playbook and HTC EVO View 4G will come to a halt and supplies will run down within the coming weeks, according to the EOL list obtained by SprintFeed. Both tablets will be phased out by the end of of January, possibly leading to the announcement of an LTE tablet from the Overland Park-based company. At this year's Consumer Electronics Show, Sprint announced two new LTE-powered smartphones, the Samsung Galaxy Nexus and LG Viper, which will launch some time this spring. The company is looking to roll out its 4G LTE network by mid-2012 in select locations.
Tags: 4G LTE, BlackBerry Playbook, EVO View 4G, HTC, LG Viper, RIM, Samsung Galaxy Nexus, Sprint
Make sure you don't have any of these 17 sketchy Google Play apps on your phone
By Andy Meek 3 days ago
Best Buy has so many great deals today – here are the 10 best ones

redpajama_set_name: RedPajamaCommonCrawl


What is the best internet provider in Bonadelle Ranchos-Madera Ranchos?
As one of the many census-designated places in the Fresno metropolitan area, Bonadelle Ranchos-Madera Ranchos has over 8500 residents. No matter which part of the city you live in, you can enjoy city amenities, suburban safety, and a number of other exciting attractions. One of the top priorities for those living and working in Bonadelle Ranchos-Madera Ranchos is high speed Internet access.
A popular choice for those living in this region is AT&T. Through AT&T, local homes and businesses can enjoy high speed DSL and fiber optic service with high connection speeds. The network covers the entirety of Bonadelle Ranchos-Madera Ranchos and stretches to include other parts of the Fresno area.
Another high speed option available to you is Xfinity. This is one of the fastest networks in the area, offering cable download speeds up to 250 Mbps. Like AT&T, Xfinity brings service to all of Bonadelle Ranchos-Madera Ranchos and many of its neighboring communities.


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TO BE SUCCESSFUL, MICROSOFT MUST ENTICE DEVELOPERS TO BUILD APPS THAT USE ITS CLOUD SERVICES. SEVERAL KEY ANNOUNCEMENTS AIM TO DO JUST THAT.
If you search Google or Bing for "Steve Ballmer developers," the first result is likely to be a video of the former Microsoft CEO manically chanting developers, over and over again. Despite the disturbing insanity of the presentation, the message was, and still is, correct. Microsoft, and every other software maker and device manufacturer, needs developers to be successful.
While Steve Ballmer obviously knew this (just check the video), he failed to understand what would bring independent and enterprise developers into the Microsoft fold. Under the leadership of current CEO Satya Nadella, Microsoft has transformed itself from a proprietary purveyor of software to a platform-neutral cloud-based software-as-a-service provider and developers all over have started to notice.
In November 2016, at its annual Connect(); conference, Microsoft made three important announcements designed to energize enterprise developers and drive more use of the Microsoft ecosystem of Azure, Windows 10, and Office 365:
Microsoft joined the Linux Foundation as a Platinum Member.
Google joined the .NET Foundation.
Microsoft worked with Samsung to enable .NET developers to build apps for Samsung devices.
Steve Ballmer's mantra of developers, developers, developers has been replaced with Satya Nadella's mobile-first, cloud-first strategy—and these three announcements exemplify that new way of thinking.
By allowing developers to use more tools regardless of their preferred platform, the Microsoft ecosystem becomes a more desirable place for the building of cross-platform applications and services. Whether you are an old-school developer working exclusively in Linux or you are all in with Azure, Microsoft wants you building apps for its ecosystem.
LINUX AND THE EVIL EMPIRE
When the news broke that Microsoft had joined the Linux Foundation as a Platinum Member, some of my "open source is the only way" friends seemed slightly perplexed. There is still a large part of the open source community that looks upon Microsoft as the leader of an evil empire. Those developers are confusing the old Microsoft with the new Microsoft.
For Apple, Alphabet (formerly Google), and Microsoft, it is all about the cloud services these days. Those three companies, and a few others, know that the future of software is as a service. Apps must be designed for a mobile device, must be cross platform, and must be able to access cloud services. In Microsoft's case, preferably it's cloud services.
A lot has changed since 2008, when Steve Ballmer sweated his way to a viral video. We are living in a different world now. A world where software is no longer a proprietary system that developers must be drawn into kicking and screaming, but a service that everyone must be able to access using whatever tools they want to use.
In a mobile-first, cloud-first world, there is no other way to conduct business. Microsoft continues to take the steps necessary to create a universal and inclusive ecosystem where all developers are welcome regardless of what tools, platform, or programming language they choose to use. Enterprises around the world demand that kind of flexibility and Microsoft is looking to provide it, even if it means openly collaborating with the open source community.
WHAT DEVELOPERS NEED TO KNOW ABOUT IOT


Researchers have discovered that New Caledonian crows and kea parrots can learn about the usefulness of objects by playing with them - similar to human baby behaviour.
It has long been thought that playful exploration allows animals to gather information about their physical world, in much the same way that human infants learn about their world through play.
In one of the first direct tests of this hypothesis, scientists studied two bird species, the New Caledonian crow and the kea parrot, to understand how they interact with objects before, during and after a task involving that object.
Dr Katie Slocombe, from the University of York's Department of Psychology, said: "Both species of bird are known for exploring objects in different ways. The New Caledonian crow use objects in the wild and the kea parrot is known for often being destructive in its play back in its native New Zealand.
The team presented the birds with blocks and ropes of different colours, weights and patterns to explore and play with, before presenting a task where they had to collapse a platform with a ball and retrieve a reward from a pipe with a stick. The ball and stick where later replaced with the blocks and ropes to see whether they could choose the right tool from their earlier play session to complete the task.
The team suggests that applying this simple test to other species may shed more light on the different functions of play and exploration and its relation to tool use and physical problem solving.
Megan Lambert, PhD student at the University of York, said: "This type of 'latent learning', which occurs without any reinforcement, is thought to be particularly important for animals to be able to use objects as tools in a variety of contexts for creative problem-solving.
"Although the birds appeared to learn from their exploration, we found no evidence that the birds changed the way they interacted with the objects after learning they could be used as tools.


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Former Notre Dame QB Malik Zaire questions Ohio State's Strength
Two college football superpowers, Ohio State and Notre Dame will meet in the Horseshoe to open the 2022 season this Saturday. Before the game former Fighting Irish quarterback Malik Zaire took to Twitter to question the strength of the Buckeyes.
In his tweet, Zaire also attached a video of ESPN college football analyst Paul Finebaum. In the video, Finebaum skeptically responded to Marcus Freeman's comment that the Irish were 17.5 point underdog to the Buckeyes.
"All this chatter for a 'top' ranked Ohio State team that won't play on major TV after ND cause schedule is full of bottom dwellers," Zaire tweeted.
On Wednesday morning, Zaire also took on Ohio State fans. His tweets have since drawn comments from others.
"Ohio State fans get so hype but y'all wasn't even the best team in Ohio last year! Lol CINCY was" Zaire wrote.
Zaire was referring to the Cincinnati Bearcats. The team is the first-ever Group of Five team to make the College Football Playoff after they finished last season undefeated.
Zaire did not stop the trash-talk there. He launched more comments regarding Ohio State. The latest of his tweets criticized former Ohio State quarterbacks JT Barrett, Cardale Jones, and Braxton Miller.
"ino yall worried about Saturday! But I promise y'all can still make it to the playoffs after this whoopin!" He said on Twitter.
It was responded by Edmonton Elks quarterback Cardale Jones, challenging Zaire to make a bet on the game. Zaire said the Fighting Irish would win the game over the Buckeyes.
"Listen if this Saturday 9/3 was a 7on7 competition then of course Ohio state is an easy choice… but until I hear something bout y'all actually being able to shed blocks and tackle or hold up front against a challenge! What am I lying about? we got better matchups," Zaire said.
Ohio State Vs. Notre Dame
The Buckeyes and Fighting Irish have an equal opportunity to win since both teams are in the top five of the AP polls. The game will decide their fate in the College Football Playoff.
Prior to the game, the teams met just six times. The Fighting Irish won the first two competitions, while the other four were in the Buckeyes' hands. The most recent match was in 2016 at the Fiesta Bowl, where Ohio State won 44-28.
The Buckeyes showed a lot of improvement last season. The team's offense was unstoppable. It succeeded to finish no. 1 in total offense and scoring. Moreover, it also took second place in third down conversions and third place in passing.
Ohio State also tried to strengthen its defense by bringing in Jim Knowles from Oklahoma State. This suggests an aggressive and defensive back-led approach will be the Buckeyes' strategy of choice this season.
On Notre Dame's side, Tyler Buchner is one of the best players on the team. He showed a significant role in big moments last year. The team also has Lorenzo Styles, who had an outstanding performance last season, including a 100-yard showing in the Fiesta Bowl. In addition, Notre Dame also has other great players like Chris Tyree, Michael Meyer, and many more.
The winner of the game will have a significant advantage for playoffs while the falling team will have to make a comeback in the round of the top-four.


A new Baltic-based LNG production plant is expected to export a first cargo within weeks as Russia starts to supply its first volumes aimed at the LNG bunkering sector.
Russian energy company Novatek, which is working with Gazprombank on the project, has started production at its Cryogas-Vysotsk LNG plant. The 660,000-tonne-per-annum facility is 150 kilometres (93 miles) north-west of St Petersburg on the Baltic Sea coast.
Some of the first volumes are scheduled to be shipped to Finland. Anthony Veder's 18,000-cbm Coral Energice (built 2018), which is on charter to Gasum serving the infrastructure company's terminals in Pori and Tornio, is expected to lift the first cargo.
Mark Gyetvay, deputy chairman of Novatek's management board, said earlier this year that the company had contracted about 30% of the plant's LNG volume.
He detailed that Finland and the Baltic states will be key sales markets and said the terminal will also focus on the bunkering of LNG-fuelled vessels.
Novatek officials said this month that the plant, which uses pipeline gas as its feedstock, would launch operations with its first 660,000-tonnes-per-annum (tpa) train. But they said a decision on two more production trains, which would add a further 1.2 million tpa of capacity, would be taken next year.
In October last year, Novatek and Belgium's Fluxys signed a deal with Rostock Port to build a mid-scale, 300,000-tpa LNG bunkering terminal in the port of Rostock in Germany, which the Russian energy company said would be supplied from Cryogas-Vysotsk.
"One of our LNG strategic initiatives is to develop small to medium-tonnage projects to target niche markets and customer segments," Leonid Mikhelson, Novatek's chairman of the management board, said.
This story has been amended since publication to reflect that the Coral Energice is chartered by Gasum.


"Of course if you do decide to come into my bedroom, you better not be wearing any of that," House remarked, motioning to the clothes she was wearing as well as the clothes he'd thrown to her.
Cameron replayed the message five times, just to make sure she'd heard it right the first four times.
Cameron blinked. She still wasn't sure what had happened.
She and Chase had gotten into a huge fight the night before about her reluctance to commit. He thought she was afraid and she kept telling him that she was invested in their relationship...she just had a weird way of showing how much she cared.
He'd stormed out and she never called to fix things like she usually did. They avoided each other at work and now this...this message. She wasn't sure what he meant. Were they broken up? Why did he get to decide that? What was he really asking for? It was all so ambiguous.
Pausing by the door, she wondered if she shouldn't change her plans and opt for a night in with Ben & Jerry's to comfort her. Suddenly, a night out seemed like the absolute last thing she wanted to be doing. She wasn't even sure if she was upset, or angry, or perhaps hurt.
She glanced down at the cell phone in her hand, wondering if she should call Foreman and cancel. It was just dinner and drinks. It was no big deal.
She shook her head, reaching for her jacket. If it was no big deal, then she shouldn't cancel. She wouldn't cancel just because of Chase. He'd be sitting there grinning about how he had finally hurt her, and she wasn't about to give him that satisfaction. If he wanted to break up with her answering machine, then fine. She wasn't going to sit at home and wallow, even if she didn't feel like facing the general public just yet.
"Where's Chase?" Foreman asked as Cameron rushed over to the table, blonde hair flying wildly.
Cameron raised an eyebrow reproachfully, scanning the crowd. "I uh..." She hadn't been prepared for this. She had already been running late for dinner when she noticed Chase's message, and after replaying it incessantly, she'd added an extra twenty minutes onto that tardiness. Yet, here she was, and Chase, well, Chase was very much not in sight.
"Sorry!" Thirteen said, rushing in and joining the two at the tall pub table. "Kutner had car trouble so I had to drive him home," she explained quickly.
Cameron smiled at her in acknowledgment, grateful for her perfectly timed interruption.
"It's fine," Foreman insisted as she slid into the chair next to him.
"Where's Chase?" Thirteen asked, more out of habit than genuine concern.
Crap, Cameron thought. And Thirteen had been doing so well.
"You didn't tell me she was going to be here!" House exclaimed dramatically as he and Wilson entered the restaurant.
Cameron shot Foreman a knowing look. She hadn't known House was coming out.
"He claimed he was offended that we didn't invite him," Thirteen explained quickly, in a hushed tone.
Cameron tried to compose herself as Wilson and House made their way over to the table. House eyed the only two open seats, both on either side of Cameron. He made a face.
"You're splitting up the dream team," he exclaimed sarcastically.
Cameron kicked him from under the table.
"Didn't think to check in on him?" House asked, curiosity peaked.
Cameron fumed inwardly, turning sharply to meet his gaze. "He probably wouldn't answer," she remarked, giving away the information she knew he was searching for.
"What can I get for you?" the waitress asked. She flashed an all too eager smile at Wilson.
"I'll have a Heineken," Foreman began, than turned to Thirteen. "Gin and tonic?" he asked, and she nodded in response. He looked at Cameron, squinting as if trying to remember. Cameron usually opted not to drink. But tonight was different. She was trying to hold herself together, and Foreman knew her well enough to know that much. Tonight was a night for alcohol. "Make it two Heineken's," he insisted, nodding to the waitress. Cameron grinned.
Foreman ignored House as he and Wilson placed their orders.
"For what?" Wilson asked, usually in on the betting pools.
"House," Foreman warned, knowing full well it wouldn't help.
Thirteen shifted uncomfortably in her seat, eyeing the table as if it had suddenly become very interesting.
"What?" Cameron asked, feeling like all of the tension was being cast onto her.
"Oh nothing," House replied, apparently reveling from something.
Cameron sighed. "What was the bet?" she asked, now certain that it had involved her in some way.
"No, that was me," Foreman insisted, raising his hand.
"Hey, at least I gave you guys another year!" she defended.
"Wouldn't tell us," Foreman and Thirteen said in unison.
"One that would never come true," House remarked, emphasizing the word never theatrically. He turned back to Cameron. "So tell me...did he cry?" he asked dramatically.
"You and Chase didn't break up?" Foreman asked carefully, and Cameron could almost feel him calculating her response, wondering if he had summed up her emotional state inaccurately.
Cameron smiled gratefully at Wilson, but House being House figured it all out on his own.
Cameron took a long gulp of her beer. "It's...he...it's complicated," she insisted.
"So you guys didn't break up?" Thirteen asked.
"But you guys aren't together?" Foreman asked.
"Ouch," Thirteen and Wilson said in response.
It had taken almost ten minutes, but Cameron had been able to change the subject. Foreman and Thirteen left right after dinner and Cameron had excused herself to the bar, not wanting to be the third wheel with Wilson and House. Actually, she was avoiding House and his sarcasm. She wasn't in the mood for his jokes, but she also wasn't ready to go home.
"Another beer?" the bartender asked.
Cameron nodded eagerly, playing idly with the round coaster in front of her.
"I got it," the guy next to her called, winking at her.
Cameron scrunched up her face in disgust. He had been hitting on her nonstop since she'd sat down at the bar.
"No thanks," Cameron said, turning away before he could say anything else.
The bartender exchanged a knowing smile with her as he handed her the drink.
"Thanks," she mouthed, raising it to her lips.
"Looks like I'm d.d. tonight," a voice behind her said.
Cameron spun around, matching voice with face. "Do you even know what the qualifications of a designated driver are?" she asked.
"I haven't had that much," Cameron lied. She had. She assumed she'd call a cab to take her home.
"I'm not going on your motorcycle," Cameron insisted. The thought of it made her queasy.
Cameron was unable to refute that logic, so she quickly finished her beer, pushing a fifty towards the end of the bar.
"Fine," she said, grabbing her jacket.
Cameron smirked. "Just drive," she insisted, tossing him her keys as she ambled through the parking lot to her car.
"That's why I don't watch tv," she remarked, her voice muffled from the fabric of the pillow. She waited until he thought he'd sustained her before ripping the pillow from his grasp.
House's eyes lit up, amused. "Got any phone numbers?" he teased.
House grabbed her by the chin, forcing her to look into his eyes. She gasped, startled by his forcefulness and fell silent at his touch.
He cracked a smile. "Don't ever insult this show again," he warned, letting her go.
Cameron laughed, reaching into the bowl of popcorn. "I'm so hungry," she remarked.
House laughed, turning the television off. "Night!" he remarked, propelling himself up with his cane.
Cameron grinned. "Exactly. You can't shake me, but I can shake you..." She stopped. "Wait...did that...I don't know if that said exactly what I meant to say...." She paused, rubbing her head, then surprised House by laughing.
House shook his head, disappearing into his bedroom and then returning with a long sleeved flannel shirt and a pair of sweat pants. "Here," he remarked, tossing them at her. Cameron met his stare with confusion. "Well, you can't sleep in that," he insisted, eyeing her outfit.
Cameron looked down at her dark blue silk blouse and black skirt. "Um, thanks," she replied, her usual vulnerability breaking through the alcohol induced carefree front she'd created.
Cameron snorted. "Wasn't planning on it," she told him.
"House," she began slowly, clutching the loaned clothes as she made her way over to him. She took exaggeratedly small steps, and she could tell as she moved closer that she was making him nervous. He had no idea what drunk Cameron would do.
She arched her neck back so that she was looking straight up at him, her breasts pushed into his chest. She leaned in, eyes remaining firmly on his.
"Get over yourself," she whispered, smiling coyly as she steered past him and into the bathroom.
It was six when she woke up, head pounding and body pleading for her to shut her eyes. But, hungover or not, she was entirely too practical to fall back into the temptation of sleep, and reluctantly, she hoisted herself up off of the soft, firm...bed?
She froze, taking a moment to collect herself before allowing her head to whip around, panicked. She was in House's bedroom. In House's bed. Under House's sheets.
She jumped up and onto the floor and was nearly to the door when she realized something was irrational about her terror. Yes, she was in House's bed, but he was certainly nowhere to be found.
That's when it came flooding back to her. She'd gone into the bathroom to change and when she came back out, House had set up camp on the couch. He feigned being asleep for about two minutes, until he couldn't resist throwing yet another couch pillow at her. She insisted that he take the bed, and he turned over onto his side, resting his weight on his good leg, and told her to go to hell.
She'd smiled but knew better than to thank him.
Grinning from that memory, she slipped on her shoes and grabbed her clothes from the evening before, setting them on a chair with her purse. She quickly made the bed, knowing that this effort would make House cringe, and then she grabbed her things, heading out into the living room.
He was sleeping soundly, looking oddly small under the light cotton blanket draped over his body. Cameron smiled at the sight, then disappeared into the kitchen in search of paper. She found a small pad of post-its and grinned at her luck. She dug through her purse until she found a pen and quickly scribbled a small note.
I should tease you and call you 'chivalrous' but we both know you're sleeping on the couch because you secretly know you couldn't handle me.
She scrutinized the note for a moment. She hadn't meant to use her first name, but now that it was there, in writing, it looked like it belonged. Still, she felt it somehow made the note all the more personal and worried he might get the wrong idea.
Despite her minor worries, she ripped it off of the stack of scratch paper and walked into the living room, wondering where to put it. She considered the bathroom mirror, or his vicodin bottle, or perhaps even the tv, but as he let out a slight snore, proving that he really was dead asleep, she thought of a better place.
And that was why when House woke up an hour later, wondering why the entire world was bathed in pink, he found his forehead had been attacked by a crazed woman who decided it would be fun to leave a note stuck to his skin.
Even if she hadn't been the only other person in the apartment, he knew those loopy g's cold.


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Expert Profile - Franco Carlotto
Franco Carlotto
Fitness Expert Expert stats
Years Training: 27
Six-time Mr. World Fitness
Creator of the Carb Cycle by Franco Carlotto
Founder of Optifitness and Fitness for Kids
Carried Olympic Torch through Lausanne, Switzerland, June 2004
"Optimal fitness is not a sprint but a journey. Your body doesn't just think in calories, but more in nutrients. Once you implement the carb cycle philosophy, you can be synchronized with any goal or food preference in achieving and maintaining a fit form and healthy lifestyle. My goal is to educate and teach people how to eat, exercise and think right about fitness − and especially carbohydrates."
Carlotto is Swiss-Italian and found his passion for fitness at the age of 11 when he set the goal to learn everything he could about fitness. His dream was to become a World Champion and it became a reality 15 years later. After years of trying and testing countless diets and fitness methods, Carlotto eventually discovered "the truth about fitness" and won the prestigious Mr. World Fitness competition six years in a row. In addition, Carlotto was No. 1 on the World Fitness Federation World Ranking list from 1996−2004, a record that has made him one of the most successful and recognized fitness athletes ever as well as an internationally recognized fitness model and expert.
As a fitness expert, Carlotto has been a spokesperson, official partner, speaker, or consultant for prestigious groups including: The Department of Health Services, American Cancer Society, Centers for Disease Control and Prevention, The Boys and Girls Club, The American Heart Association, Special Olympics and The March of Dimes. He is the author of Franco Carlotto's Carb Cycle and Fitness for Kids − Because Children are our Future and his work has also been published in newspapers and magazines such as GQ, Fit for Fun, Bild and Swiss Illustrated.
Having spent the past 27 years dedicated to the study of fitness and nutrition, Carlotto created the Carb Cycle system to win all of his championship titles as well as help people all over the world get and stay in shape using his knowledge and unique methods of eating carbs the right way.
Carlotto resides in Los Angeles, Calif., teaching his fitness philosophy and Carb Cycle system to everyone, from celebrities and corporate executives to housewives. Simultaneously, he is building Fitness for Kids into a worldwide organization for upcoming generations.
Carb Cycle