“Hemoglobin is in some ways the most interesting of all substances.”
Linus Pauling. 1936.

“The item of $7,500 for apparatus, supplies, animals would permit us to use the large number of animals required for some of our projected researches, and should permit also the construction of a Tiselius apparatus for the electrophoretic separation of antibody fractions by the suggested method of combination with charged haptens, and for other investigations."
Linus Pauling, budget request letter to Warren Weaver. January 2, 1941.

“On the basis of the information available to me, I have formed the opinion that oxypolygelatin solution…may well be a thoroughly satisfactory blood substitute, which could be manufactured cheaply in large quantities. It is probably superior to gelatin itself with respect to fluidity of solution, retention in blood stream, and osmotic pressure.”
Linus Pauling, letter to Walter B. Cannon, National Research Council. March 14, 1944.

“Science cannot be stopped. Man will gather knowledge no matter what the consequences – and we cannot predict what they will be. Science will go on – whether we are pessimistic, or are optimistic, as I am. I know that great, interesting, and valuable discoveries can be made and will be made…But I know also that still more interesting discoveries will be made that I have not the imagination to describe – and I am awaiting them, full of curiosity and enthusiasm.”
Linus Pauling. From 1947 Lecture at Yale University, "Chemical Achievement and Hope for the Future." Reproduced in Science in Progress. Sixth Series. Ed. George A. Baitsell. 100-21, 1949. October 1947.

“It appears, therefore, that while some of the details of this picture of the sickling process are as yet conjectural, the proposed mechanism is consistent with experimental observations at hand and offers a chemical and physical basis for many of them. Furthermore, if it is correct, it supplies a direct link between the existence of “defective” hemoglobin molecules and the pathological consequences of sickle cell disease."
Pauling, Itano, Singer, and Wells. 1949.

“The rapidity and simplicity of this test suggests that it would be useful as a clinical laboratory procedure for diagnosing sickle cell anemia and sickle cell trait.”
Harvey A. Itano and Linus Pauling. From "A Rapid Diagnostic Test for Sickle Cell Anemia," Blood, 4(1): 66-68, 67. January 1949.

“Our postulate provides an obvious explanation of the action of oxygen in preventing the sickling of sickle-cell-anemia erythrocytes. We have visualized the sickling process as one in which complementary sites on adjacent hemoglobin molecules combine. It was suggested that erythrocytes containing oxyhemoglobin or carbonmonoxyhemoglobin do not sickle because of steric hindrance of the attached oxygen or carbon monoxide molecule. This steric hindrance effect might be the distortion of the complementary sites through forcing apart of layers of protein, as is suggested by the isocyanide experiments.”
Linus Pauling and Robert C. C. St. George. 1951.

“I believe medicine is just now entering into a new era when progress will be much more rapid than before, when scientists will have discovered the molecular basis of diseases, and will have discovered why molecules of certain drugs are effective in treatment, and others are not effective.”
Linus Pauling, interview with Portland Oregonian. February 13, 1952.

“The idea of Dr. Linus Pauling that an abnormal hemoglobin molecule might be responsible for the sickling process initiated the study of the hemoglobin molecule in hereditary anemias.”
Harvey A. Itano. From Minot Lecture, "Clinical States Associated with Alterations of the Hemoglobin Molecule," Archives of Internal Medicine, 96: 287-97, 295. 1955.

“The discovery by Dr. Itano of the abnormal human hemoglobins has thrown much light on the problem of the nature of the hereditary hemolytic anemias, and has changed these diseases from the status of poorly understood and poorly characterized diseases into that of well understood and well characterized diseases.”
Linus Pauling, nomination of Harvey Itano for the Theobald Smith Award. 1955.

“Dr. Pauling explained the reasons behind his developing interest in the field of mental deficiency. His research in hematology has now developed this area to the point where other researchers have taken over and will carry on."
Meeting Notes. July 1955.

“The manufacture of abnormal molecules…is determined by the genetic constitution of the patient; the disease is inherited. A disease of this sort, caused by molecules of abnormal structure present in the patient in place of the molecules of normal structure that are present in normal human beings, is called a molecular disease.”
Linus Pauling's definition of Molecular Disease, from "The Molecular Basis of Genetics," American Journal of Psychiatry, 113: 492-495, 492. 1956.

“It is astounding that the difference in structure is so small – only about a dozen atoms out of 10,000 in the molecule are different. On such small atomies man’s fate depends!”
Linus Pauling commenting on Ingram's Results. 1958.

“As more and more tests for heterozygosity are developed, predictions can be made with greater and greater reliability about the probability of birth of defective children, and advice can be given to prospective spouses or parents about the desirability of their contributing to the welfare of the human race as a whole by preventing the transmissions of seriously defective genes to the next generation."
Linus Pauling. From “Molecular Structure and Disease,” Disease and the Advancement of Basic Science, Ed. Henry K. Beecher, pp. 1-7, 7. 1960.

“It thus appears possible that there would be no evolution without molecular disease.”
Emile Zuckerkandl and Linus Pauling. From “Molecular Disease, Evolution, and Genic Heterogeneity,” Horizons in Biochemistry, Eds. Michael Kasha and Bernard Pullman, pp. 189-225. 1962.

“In the United States about 10 per cent of the Negro population (and a much smaller percentage of the remaining population) carry the gene for sickle-cell-anemia hemoglobin or the somewhat similar gene for hemoglobin C. About 1 child in 400 born in the Negro population in the United States inherits two of these genes and in consequence suffers from the very serious disease, sickle cell anemia (or the related diseases involving the hemoglobin-C gene).”
Linus Pauling. From "Our Hope for the Future", Birth Defects, 167-68. 1963.

“The demonstration that sickle cell hemoglobin differs in electrophoretic mobility from normal hemoglobin led to the entitled inference: “Sickle cell anemia, a molecular disease.” This astonishingly simple concept is of fundamental importance to medicine for the ultimate understanding of the origins of sickness, and to biology for the insight into what genes do. In the author’s words, “This investigation…reveals a clear case of a change produced in a protein molecule by an allelic change in a single gene involved in synthesis.”
Samuel H. Boyer IV’s introduction to a reprint of “Sickle Cell Anemia, a Molecular Disease,” Papers on Human Genetics, 115-25. 1963.

“It is probable that the sickle cell gene represents a first step in the process of evolution toward the development of a mutant human being with effective protection against malaria and without the handicap of having half of the children die of either malaria or sickle cell anemia."
Linus Pauling. From “Our Hope for our Future,” Birth Defects, p. 168. 1963.

“In 1949, application of methods of physical chemistry directly to the study of a protein produced by a mutated gene led Pauling, Itano, Singer and Wells to identify the specific change in the protein brought about by the gene. The discovery of the first of the abnormal human hemoglobins which they described as causing a “molecular disease”-sickle cell anemia-was followed the identification of a large number of other proteins, each of which owed its difference from normal structure to a mutated gene. Ingram then showed that the change due to the mutation, in the case of each of two abnormal hemoglobins, was confined to a single amino acid residue at one point in one of the polypeptide chains composing the globin. There could be no doubt that genes controlled protein structure by specifying the sequence of amino acid residues in the polypeptide chains. The assumed basic functional correspondence was then altered from “one gene-one enzyme” to “one gene-one polypeptide.”
Geneticist L. C. Dunn. From "Old and New in Genetics," Bulletin of the New York Academy of Medicine, 40(5): 325-333, 329. May 1964.

“You know, hemoglobin is a wonderful substance. I like it. It’s a red substance that brings color into the cheeks of girls, and in the course of my hemoglobin investigation I look about a good bit to appreciate it.”
Linus Pauling. From "Science and World Problems," Enzymes in Mental Health, Eds. Gustav J. Martin and Bruno Kisch, 13-18, 13. 1966.

“It [hemoglobin] is a good substance from the standpoint of a chemist, because of its availability. All you need to do is to catch somebody, introduce a hypodermic needle and draw out a sample of blood. A standard victim of this practice, weighing perhaps 120 pounds (it's easier to catch them small!) contains in the red corpuscles in his blood one and two-tenths pounds of hemoglobin.”
Linus Pauling. 1966.

“Hemoglobin is complicated enough to be interesting. I began research in the nature of hemoglobin in 1935, and now 31 years later, I am still entranced by this wonderful molecule."
Linus Pauling. From “Science and World Problems,” Enzymes in Mental Health, p. 14. 1966.

“It [hemoglobin] is a good substance from the standpoint of a chemist, because of its availability. All you need to do is to catch somebody, introduce a hypodermic needle and draw out a sample of blood. A standard victim of this practice, weighing perhaps 120 pounds (it's easier to catch them small!) contains in the red corpuscles in his blood one and two-tenths pounds of hemoglobin.”
Linus Pauling. 1966.

“I have suggested that the time might come in the future when information about heterozygosity in such serious genes as the sickle cell anemia gene would be tattooed on the forehead of the carriers, so that young men and women would at once be warned not to fall in love with each other.”
Linus Pauling, letter to S. Leonard Wadler. August 15, 1966.

“He [Zuckerkandl] found that in the beta chain of the human and the beta chain of the horse, for example, 20 of the 146 amino acids are different; but with human and gorilla, only one is different. It is the same amount of difference, just one amino acid residue, as between ordinary humans and sickle cell anemia patients, who manufacture sickle-cell-anemia hemoglobin."
Linus Pauling. From “Medicine in a Rational Society,” Journal of the Mount Sinai Hospital of New York, 36: 194-99, 196. 1969.

“The National Institutes of Health have indicated that research into this disease is to be more than adequately funded over the next several years and it is hoped that the three year contract applied for will be funded early in the summer of 1972. It is worthy of note that the project director for this research performed pioneering work in the molecular understanding of this disease and has continued to play an influential role in continued research to date.”
Excerpt from grant application, “The Involvement of Humoral, Metabolic, and Molecular Factors in Sickle Cell Crisis.” 1972.

“In my current Institute [Linus Pauling Institute] there are the problems of any new experimental and research institute. It seems to be possible to get grants for our more conventional work but not for the problems that I would like to attack, which I consider to be the more imaginative ones.”
Linus Pauling. From interview by David Ridgway for Aug. 1976, Journal of Chemical Education, 53: 471-76, 475. June 20, 1975.

“I remember asking a new graduate student, Harvey Itano, what his research problem was. He said he was going to test your hunch that there was a difference in hemoglobin molecules between normal people and those with sickle cell anemia. I thought that was a crazy idea; a complicated human disease could not have any such simple cause. And so I learned to respect bold simple ideas – especially those conceived by Linus Pauling.”
Norman Davidson, letter to Linus Pauling. January 26, 1976.

“I think that it is the duty of scientists to help their fellow citizens to understand the problems, and to give them the benefit of their own knowledge about the scientific aspects of the problems. In addition, however, to this work of helping to educate their fellow citizens, scientists have, I think, the obligation to express their own opinions, in order to help their fellow citizens.”
Linus Pauling. From interview with Harald von Troschke, “Preliminary Script for German TV Program.” May 26, 1976.

“So far as I am aware, my idea in 1945 that human hemoglobinopathies exist was the first time that this idea had been expressed. Our 1949 paper was the first paper showing that there is in fact a human hemoglobinopathy, and it was followed by work leading to a great development of this field. My earlier work on the magnetic properties of hemoglobin was responsible in large part for the development of the now-accepted ideas about the binding of oxygen and carbon monoxide.”
Linus Pauling, letter to C. Lockard Conley. August 1, 1978.

“The hemoglobin molecule, with its striking color and its property of combining reversibly with dioxygen, seemed to me to be especially interesting.”
Linus Pauling. 1980.

“People have said to me if I hadn’t received the Nobel Prize in Chemistry probably I would have gotten the Nobel Prize in Medicine for having discovered molecular diseases. And perhaps so. But it doesn’t bother me. Why should I discover everything? I’m satisfied.”
Linus Pauling during an interview. 1980s.

“Ortho means “right” – the right molecules in the right amounts. Orthomolecular medicine is the use of the right molecules or orthomolecular substances that are normally present in the human body in the amounts that lead to the best of health and the greatest decrease in disease. It is the most effective prevention in the treatment of disease.”
Linus Pauling. From interview by Deborah Kesten. Healthline. April 1983.

“I went to New York and gave a seminar at the Rockefeller Institute for Medical Research, in 1936. And at that time, I asked the director, Simon Flexner, to send Alfred Mirsky and his family to Pasadena to be with us for a year, because of my interest in hemoglobin. So Mirsky came. Mirsky was astonished that I would have the temerity to approach Flexner—I was a brash young man, I think—and then astonished that it worked out!”
Linus Pauling in an interview with John L. Greenberg for Caltech archives. p. 33. May 10, 1984.

“I’d built up this great research organization in structural chemistry, and I had discovered molecular diseases there at the Institute.”
Linus Pauling reflecting on resigning from Caltech. From California Institute of Technology Oral History Project, John L. Greenberg. May 10, 1984.

“Life is too complicated to permit a complete understanding through the study of whole organisms. Only by simplifying a biological problem – breaking it down into a multitude of individual problems – can you get the answers. In 1935, for example, Charles Coryell and I made our discovery about how oxygen molecules are attached to the iron atoms of hemoglobin, not by getting a cow and putting it into our magnetic apparatus, but by getting some blood from the cow and studying this blood.”
Linus Pauling, interview with Neil A. Campbell, Bioscience, v. 36, no. 11. December 1986.

“If the bomb testing had gone on at the same rate for a few more years, it would have meant that,…according to my calculations, which seem to have been essentially right, millions of children, infants, would have been born with gross physical and mental defects that otherwise would not have had the defect and millions of people would have died of cancer at an earlier age than otherwise.”
Linus Pauling, interview with Neil A. Campbell, Bioscience, v. 36, no. 11. December 1986.

“Many orthomolecular substances are so free from toxicity that they show beneficial effects over a 10,000-fold range of concentrations. Yet if you take even ten times the amount of aspirin that many patients take, for example, you’d be dead; hundreds of people do die every year from aspirin poisoning. And all of the other major drugs are highly toxic as well.”
Linus Pauling, interview with Neil A. Campbell, Bioscience, v. 36, no. 11. December 1986.

“Well, I thought that was a pretty nice idea that I had in 1945, about molecular diseases.”
Linus Pauling. From interview with Nancy Touchette for "The First Molecular Biologist," Journal of NIH Research , vol. 2. 1990.

“…[M]y recommendation to young people, which I have been making for fifty years, is that if you want to go into biology, biochemistry, molecular biology, why don’t you start out by majoring in physics and chemistry and mathematics and then move on later? I’ve even recommended…to students interested in biology to take the Ph.D. in chemistry, rather than biology, and then…start work in…plant physiology or some other field. With your basic understanding you will be able to be successful in this field.”
Linus Pauling, interview with Wayne Reynolds. November 11, 1990.

Making an analogy with antibodies, we might say that perhaps these patients manufacture an abnormal sort of hemoglobin molecule that is capable of combining with itself; that has a region on one side that just fits neatly onto the region on the other side of a similar molecule. The molecules of hemoglobin would clamp onto one another, the second one onto the first one, the third one onto the second, and so on, forming a long rod. This long rod would line up with similar rods; general forces of attraction would bring them together, forming a long, needle-like crystal of hemoglobin, which as it grew in the red cell, would finally become longer than the diameter of the cell. Then as it continued to grow it would twist the red cell out of shape into the elongated forms that are observed.
Transcript from Audio Clip: Men and Molecules: Molecular Medicine., Analogy between antibodies and SCA process., February 26, 1962..

Narrator: A person afflicted with the disease has inherited two sickle cell genes from his parents. This realization, that the two genes manufacture the abnormal hemoglobin, set the stage for Dr. Pauling’s entry into the field of molecular medicine.Dr. Pauling: Well, when Doctors Itano, Singer, and Wells, and I published our paper in 1949, we gave it the title: “Sickle Cell Anemia: A Molecular Disease.” Now of course, in fact, one might say that any inborn error of metabolism, any hereditary disease, is a molecular disease because it involves an abnormal gene. And the gene we know, almost certainly, is a molecule of DNA, deoxyribose nucleic acid. The abnormal molecule of deoxyribose nucleic acid that is inherited by the child, prospective patient, causes the trouble for him, and the hereditary disease is accordingly a molecular disease.
Transcript from Audio Clip: Men and Molecules: Molecular Medicine., Definition of molecular disease, covers DNA and inheritance of diseases., February 26, 1962..

I believe, that, provided that enough money is put into the field of medical research and research in the sciences fundamental to medical research, it will be possible for us to make very great progress during the next few years or the next few decades in the control of disease and in the diminution of the amount of human suffering. I think in fact, that this is the way in which the transition, the economic dislocation, from a Cold War economy to a peace economy accompanying disarmament can be carried out.A great many scientists are now working on weapons or on problems connected with war and the Cold War. We need to set up, our government needs to set up, many great laboratories in which these scientists could carry on work on problems related to medicine or fundamental to medical research. This would be, then, a way, in which unemployment, of scientists, could be avoided, the economic transition could be achieved, and for the benefit of the American People.
Transcript from Audio Clip: Men and Molecules: Molecular Medicine., Rectifying the cold war economy., February 26, 1962..

Narrator: Researchers now know that the possession of one sickle cell gene can, in at least one sense, be considered an advantage. Their work has shown that people with a single gene have a high degree of protection against malaria, once considered to be the greatest disease scourge in some parts of the world.Dr. Pauling: Now of course malaria is no longer a scourge in the United States and in other countries, and so being a sickle cell heterozygote is not of any advantage, and yet the defective children with Sickle Cell Anemia continue to be born. And that is a way of getting rid of the gene now that it no longer is of value. When these defective children die, they carry two sickle cell genes out of existence; consequently the gene will slowly disappear.A man who has worked in this field, Dr. Anthony Ellison, he is an Englishman who is responsible for having shown that the sickle cell gene protects against malaria, has calculated that among the Negro population in the United States the incidence of the gene has dropped from about 20 percent to about 10 percent, at the expense of much suffering. If the children were not to be born, that would be a better way of getting rid of this deleterious gene, not at the cost of human suffering but by the use of human intelligence.
Transcript from Audio Clip: Men and Molecules: Molecular Medicine., Stopping the spread of SCA to children., March 30, 1962..

I think that it is good that young people should concentrate and work very hard on their special fields. I’m thinking especially of young men and women who are doing, say, post-graduate work, working for a doctor's degree. I think it’s good to get a broad education in the early years, including science and mathematics and the humanitarian subjects, the humanities, too. But then later on in life, I believe that it is a good thing to bottom one’s field of active interests, to include politics. I believe that it is very important for the world, now, now that science has become such an important part of the world that affects the daily life of every person and, of course, has lead to the development of great nuclear weapons that might destroy civilization, it is very important that scientists help their fellow citizens to understand what the impact of science on world affairs is, to understand in a way that the scientists can understand these questions, to understand the significance of scientific and technological developments.
Transcript from Audio Clip: See Who’s Here: Interview with Linus Pauling, hosted by Robert Phillips., Importance of focusing on specialized fields of study., December 2, 1966..

And it wasn’t until 1949 that the job was done. Now this may seem surprising, that it takes so long, well it’s like a lot of things, you don’t know whether it’s going to work out or not, and you don’t work, perhaps, don’t work as hard on it as you might, and Harvey was interested in taking a lot of courses, because there were a lot of things he hadn’t learned as a medical student that he could learn now. And we didn’t have an electrophoresis apparatus, and I got one of the graduate students working with me, to, I think he’d become a post-doctoral fellow, to start building an electrophoresis apparatus.His wife was our stock room keeper, and she, somebody asked for some ethyl-chloro-carbonate. And she went to the main, to the vault, to get this, and opened the bottle and it squirted out over her. It’s like phosgene, in its action on the lungs, and she died in a few hours; and this upset her husband greatly and it was a longer period before we had an electrophoresis apparatus.The one we had designed wouldn’t work with colored substances, and so, there was the problem of making, adapting, an adapter got built so that it worked with hemoglobin. And in the meantime, Harvey Itano was determining the properties of, various properties, of hemoglobin from these two sources, and they came out the same. He didn’t, he'd measured oxygen equilibrium curves and other oxygen, and some other properties, and kept getting the same results. But finally, by this time, John Singer, and Ibert C. Wells, were cooperating with him, and finally the electrophoresis experiments were carried out, and it was evident that sickle cell anemia had about two electron difference in electric charge than normal hemoglobin.
Transcript from Audio Clip: “Drs. Pauling and Castle: ‘Evolution of Molecular Biology.’”, Itano's work on sickle cell anemia., 1969..

I think it’s good, you know to have, to try and develop a sort of theory of the universe, while you are working, learning things. Try to couple everything that enters your head, fitted into this theory. So that you can say “well, I understand the universe;” well of course the fact is that 45 years ago, it was very hard to do this. Or the theory of the universe that you had, you were a chemist, was a very simple one, because you didn’t understand how chemical bonds were, you didn’t know what the origin of say ferromagnetism was. Everything was, sort of, was uncertain, mystical.Now as time has gone by, I think we can say that, well we can say that it seems, it seems to me that we have a very good idea about the universe. Not only about the properties of simple molecules but also of complicated molecules, high polymers, or proteins, nucleic acids, polysaccharides, even such mechanisms as the mechanism of heredity, and the younger generation starting out with a clear view of the universe, which may not be completely correct, and of course is incomplete, ought to be able to clarify the portions that still remain dark for us.
Transcript from Audio Clip: “Drs. Pauling and Castle: ‘Evolution of Molecular Biology.’”, Developing a theory for the universe., 1969..

My memory is that this was the occasion that Dr. Castle began to talk, to tell the story about what other people and he had done on Sickle Cell Anemia. And I was mildly interested in the fact that the red cells were twisted out of shape, but not very interested, because I thought the red cell is so complicated that it will be decades before anyone gets any significant understanding of it, its structure. And I wasn’t listening very hard, being polite of course, to suggest that I was paying attention when he said that the red cells do not sickle in arterial circulation or in the presence of partial pressure of oxygen, but sickle in, if the partial pressure of oxygen was low.And immediately I said to him, and the others there, I wonder if this couldn’t be a disease of the hemoglobin molecule; that the genetic constitution is such, that these people manufacture a sort of hemoglobin that is sticky, so that the molecules stick together and form long rods which then attract one another by van der Waals attraction forming a long, needle-like crystal that twists the red cell out of shape. And these mutually complimentary regions must come into atomic contact, the oxygen molecules in oxy-hemoglobin are warts on the molecule that hold them four angstroms farther apart and the van der Waals forces of attraction no longer operates effectively and so the sickling doesn’t occur in the oxy-hemoglobin.And I asked does carbon monoxide prevent the sickling; does carbon monoxide prevent the sickling? My memory is that Dr. Castle said that he didn’t know whether it did or not, but he mentioned something about carbon dioxide, but...[clarification from Dr. Castle] No, I should have said carbon monoxide today. Pauling’s (unintelligible)Well Hahn and Gillespie. Carbon monoxide. Well, it may be that you answered that it did. At any rate I said, as I recall, something like, “it’s pretty clear, it seems quite obvious that the hemoglobin and oxy-hemoglobin are behaving differently, and differently from normal hemoglobin, so I think it’s likely that this is a disease of the hemoglobin molecule. Do you think that when I get back to Pasadena, I might check up on this?” And Dr. Castle said well he didn’t see why not or who was there to stop me or something like that.
Transcript from Audio Clip: “Drs. Pauling and Castle: ‘Evolution of Molecular Biology.’”, Response to William Castle's statements., 1969..

Harvey Itano came to work with me; he had an MD degree, and was the first American Chemical Society fellow in pure chemistry given this fellowship, given to him, so that he could work for Ph.D. I asked, before he arrived, if he would be interested in looking at the blood of people with the disease Sickle Cell Anemia to see whether the hemoglobin might not be an abnormal form of hemoglobin, and he did. It was a hard job; it took three years, and Dr. John Singer and Ibert Wells began helping him, and sure enough they found that it is different.Their experiment, I’ll describe it in a simple way, if you take a little trough of salt solution, neutral pH 7, and put a drop of hemoglobin in it, the hemoglobin has a little negative charge, so if you put in electrodes, the anode here, the cathode here, positive electrode, the hemoglobin begins to move towards the positively charged electrode. You can see it, it’s red; you can see that the molecules are moving over. When they put in a drop of hemoglobin from the red cells of a patient with Sickle Cell Anemia it began to move toward the cathode, it had a positive charge instead of a negative charge, and the differences in mobility corresponded to two. This is all old, an old story, but, you know, I’m fond of it. The difference corresponds to about two electronic charges difference.They took some blood from the father of a patient and some from the mother and put it in the apparatus, and the blood from the father, half of it began moving toward the anode and half toward the cathode, and similarly the blood from the mother. This of course explained the genetics. Normal people have two genes each of which manufactures normal hemoglobin; the sickle cell patient had two genes that manufactured sickle cell hemoglobin. But the parents were heterozygotes; each parent had one normal gene and one sickle cell gene. And they set up their assembly lines independently of one another, and the one gene controlled the manufacture of normal hemoglobin and the other the manufacture of sickle cell hemoglobin. Very interesting.
Transcript from Audio Clip: Molecular Disease lectures given at SUNY, New York., Itano, Singer and Wells' work on sickle cell anemia., November 1970..

Well I think we have an understanding of the molecular basis of biological specificity. Why do people become allergic to strawberries, say, or to milk, or something like that? This is the same subject.The antibodies are protein molecules which have a region which is complimentary in structure to the antigen. For example, the benzene arsonic acid, a group that Landsteiner was fond of working with. We were able to show that the antibody molecule, the atoms in the antibody molecule, fit around this group, the heptanic group, very closely to within about a quarter of an atomic diameter, on the average.And that they bring into juxtaposition groups that are complimentary to certain groups in the heptan. For example, an electron pair donating, hydrogen bond forming atom will come up close to a hydrogen atom attached to an electronegative atom, so that a hydrogen bond is formed. And a negative charge will be brought up in the neighborhood of a positive charge in the heptanic group, and so on, all contributing to the weak intermolecular forces that operate. Now it is the shape factor that’s responsible for the specificity.We found that if antibodies were made against benzene arsonic acid, they would not combine with meta-chloral-benzene arsonic acid, that had a chlorine atom, 181 femtometers, I’m trying to learn to talk in the international system of units, 181 femtometers in diameter here, because the hole into which a hydrogen atom, 110 femtometers in radius would fit, is not big enough for the chlorine atom to get into. But if you made antibodies against the meta-chloral-benzene arsonic acid group, which have, the antibodies have a hole big enough for this chlorine atom, then the benzene arsonic acid will fit in because the hydrogen atom is smaller and it can slip into the larger hole; that sort of thing. Very, very satisfying it was to me to feel that this puzzling phenomenon of species specificity of antibodies, antiserva, could be understood.
Transcript from Audio Clip: Molecular Disease lectures given at SUNY, New York., Biological specificity work at Caltech., November 1970..

I think, I forgot to mention, I think of course that something ought to be done about this disease, Sickle Cell Anemia. Here you have fifteen hundred children born a year with this disease and doomed to a pretty poor life. And Dr. Zuckerkandl and I made a proposal; first Harvey Itano and I developed a very simple test. This drop of blood: one drop of blood with just a little variant of an existing test. But it’s no job at all, when blood tests are carried out, required for marriage licenses, say, why not check for sickling too?And then, we suggest that every young person have his genotype tattooed on his forehead, so that young people would recognize at first sight if they were incompatible in this way. In fact, we said in this paper, and then, you see they could refrain from marrying one another because if they marry one another a quarter of their children will inherit these two genes and will grossly defected, be grossly ill, will die, young, suffer and die.But they could marry normal people, and then if they married normal people, half of their children will have inherited the single gene, would be carriers like one of the parents. And so they should be encouraged to have a smaller number of children than normal, to be satisfied with one child, and then in that way, the gene which is no longer needed, because malaria is controlled by the anti-malarial drugs and the destruction of mosquito ponds and so on, in that way the gene would be got rid of. And we said this chance, twenty-five percent chance of giving birth to a defective child, is too large to allow a combination of ignorance and free enterprise in love to take care of the matter. I think that’s the way to handle that problem. Just that the heterozygotes would not marry one another, or not have children.And there’s a possibility this is being done, of course, for other abnormalities, there is the possibility that you could take a little, stick a needle in and a get a little sample of amniotic fluid and look at the cells and see whether the sickle cell gene is present in the developing embryo and abort it if it is, but this is a complicated process. Be hard to do with the sickle cell gene, but it is easy to do with Trisomy, with the extra chromosome with Mongolism, and of course, it should be done then, especially with older women who have a higher probability of this non-disjunction which produces a child with 47 chromosomes; should be done with them, especially one who, if the mother’s already given birth to a Mongoloid child.
Transcript from Audio Clip: Molecular Disease lectures given at SUNY, New York., Marriage tests and disclosing genotype information., November 1970..

You know I had a young man come from France to work with me. A friend of mine, professor of philosophy, said he had a young friend in France who wanted to study. In fact he had worked in the United States in the University of Illinois, but wanted to continue his biological work on oxidation of cells and would I accept him in the laboratory? I said yes, but when he came I talked him into working on hemoglobin because I wasn’t very interested in the Warburg apparatus and what happens with carbon dioxide coming out, and I thought, he seems like a very intelligent young man, surely he’ll get interested in hemoglobin.We made an agreement that if he would work three months on hemoglobin for me, then we would buy a Warburg apparatus and thermostats and so on and set him up. Well, he worked five years on hemoglobin. Emile Zuckerkandl is his name. He has a record. In this book, these big volumes, citation index that some computer gets out, where you can look up somebody’s name and see how many times other people have referred to his publications. Emile, Emile Zuckerkandl occurs with the record for the longest period of publications, under his name. Zuckerkandl, Emile, there come publications in Science in 1848, 1853, 1860, 1870, 1888, there's a little gap then, and then starts out again and goes on up to 1969. His grandfather, Emile Zuckerkandl, you see the computer wasn't programmed to ask how long a man lived.
Transcript from Audio Clip: Molecular Disease lectures given at SUNY, New York., Emile Zuckerkandl working on hemoglobin., November 1970..

This shows where the sickle cell gene is found. And, you know, it turns out that the sickle cell gene is found in these areas because they are malarial, and the sickle cell gene protects against Malaria. In some regions in central Africa, almost everyone is a sickle cell heterozygote. You can see what happens: the Heterozygotes marry one another, a quarter of their children are normal and die from Malaria and a quarter are sickle cell homozygotes and die of sickle cell disease, but half of them survive. Well, it’s recently that a fifty percent yield in children has been considered unsatisfactory, so this was a good step.This is the reason that the gene spread so fast; the Heterozygotes were protected. You only needed to get one of these genes to survive against Malaria. If it had been the Homozygotes, if it were a feebler mutation such that the Homozygotes were protected, it wouldn’t spread because you wouldn’t have any homozygotes. And you would have to have inbreeding for awhile before you got any homozygotes.Probably mutations of this sort take place in two steps; another ten thousand years probably would have seen the sickle cell gene disappearing and another gene taking its place with the homozygotes protected against Malaria, everybody protected against Malaria. This gene has its incidence such that you could calculate that it would only take about a thousand years for the gene to spread through a population, forty generations; a much larger number of viable survivors for people carrying the gene than those not carrying the gene.
Transcript from Audio Clip: “Abnormal Hemoglobin Molecules in Relation to Disease”. Lecture at Michigan State University., The spread of malaria affected by sickle cell disease., 1972..

I believe first that heterozygotes should be identified. And of course it is fine that there is a program going on. The test is very simple and cheap; the automated tests that Dr. Nalbandian has worked on, for example; very cheap. The heterozygotes should know that they are heterozygotes.If two heterozygotes marry one another, they should have no children, in my opinion, because a twenty-five percent chance of dooming your child to this life of suffering is too great to be acceptable to a moral person. If they want to marry one another, they should probably be sterilized so as to be sure that they would have no children. If a heterozygote marries a normal, then they won’t have to worry about the child leading a life of suffering, but half of the children will be heterozygotes, like the parent, like the one parent. And the gene, the incidence of the gene, will not die out, will not decrease.So I think that if the heterozygote marries some other person, he should be advised to have a smaller number of children than average, and then in the course of time the gene will die out, or to have no children at all. Of course, the desire to have children is a very important one.=, and I’m not willing to say that all heterozygotes who marry normals should refrain from having children.
Transcript from Audio Clip: “Abnormal Hemoglobin Molecules in Relation to Disease”. Lecture at Michigan State University., Heterozygotes marrying, having children., 1972..

There was a man in England, now at MIT, named Ingram who determined the detailed nature of the abnormality in the polypeptide chains by a method that he invented: paper, two dimensional electrophoresis and chromatography of peptides. He attacked the polypeptide chains with trypsin, a proteolytic enzyme which splits each of them into 13 short pieces of chain, about deca-peptides, perhaps. And a drop of that stuff was put on the paper, and the electric field causes it to move from the right to left and solvent flows and you get a chromatographic separation vertically.Next slide. There’s only one spot that has shifted when you go from normal hemoglobin to sickle cell hemoglobin, it’s in that vertical line, not quite at the right edge, and has moved over from the line a little to the left in the right hand picture. That turns out to be the first peptide in the beta chain, and analysis of the peptide shows that, next slide please, this shows what we see here.The alpha chain starts valine, leucine, serine, and goes on. The beta chain valine, histidine, leucine, threonine, proline, glutamate, and the sickle cell beta is valine, histidine, leucine, threonine, proline, and then valine in the sixth position, the other 140 positions are occupied by the same amino acid. This involves just one nucleotide in the gene replaced in such a way that instead of glutamic acid, valine is introduced. Glutamic acid is really glutamate, the carboxylic group is ionized COO-. Valine has a hydrocarbon side chain, so you’ve lost one negative charge. There are two beta chains in the molecule that means you’ve lost two negative charges in going to sickle cell hemoglobin.
Transcript from Audio Clip: “Abnormal Hemoglobin Molecules in Relation to Disease”. Lecture at Michigan State University., Ingram's work on sickle cell hemoglobin., 1972..

Narrator: The work on hemoglobin I believe is related to the disease, sickle cell anemia. Could you tell me how you became interested in the oddly shaped blood cells which lent the disease its name, sickle cell anemia?Dr. Pauling: Yes, I've been interested in chemistry in relation to the human being and to health and disease for a long time. In the 1930's already, I began work on the question of the nature of antibodies, antitoxins, how the human body protects itself against invasion by infection. There is a very interesting natural mechanism that is involved here. Dr. Karl Landsteiner of the Rockefeller Institute for Medical Research who is the man who discovered the blood groups and made it possible to give transfusions of blood from one human being to another, is the man who got me interested in this field of immunology. But, after some years, at the end of the war, in connection with my interest in the application of chemistry to medicine, I learned about the disease, sickle cell anemia. As soon as I learned about this disease, the very evening, it was at a dinner in New York where a medical research committee, of which I was a member, a committee that had been appointed by President Roosevelt to study medical research in the United States, was holding a meeting. At this dinner I learned about the disease, sickle cell anemia, and immediately I thought, could it be possible that this disease, which seems to be a disease of the red cell because the red cells in the patients are twisted out of shape, could really be a disease of the hemoglobin molecule? Nobody had ever suggested that there could be molecular diseases before, but this idea popped into my head. I thought, could it be that these patients can manufacture a special kind of hemoglobin such that the molecules are sticky and clamp on to one another to form long rods, which then line up side by side to form a long needle-like crystal, which as it grows inside of the red cell becomes longer than the diameter of the cell and thus twists the red cell out of shape? Well, I said to the man who was talking about the disease, Dr. Castle, "has anyone ever suggested that this might be a disease of the hemoglobin molecule?" and he said, "not so far as [he'd] ever heard." And I said, "do you think it would be alright if I were to look at this hemoglobin from these patients and see?" And he said, "I don't see why not." So when I got back to Pasadena it turned out that a young M.D., a young medical man, wanted to come to work with me in chemistry and get his Ph.D. degree. I said to him, his name is Harvey Itano, I said to him, "why don't you work on the hemoglobin that you get from patients with the disease sickle cell anemia, and see whether it is the same as hemoglobin in other human beings or it's different." Nobody had ever found any difference between the hemoglobin of one person and another before that time. Well, Dr. Itano did that together with two other young men in our laboratory, Dr. Singer and Dr. Wells. Pretty soon, it wasn't an easy job. These proteins are hard substances to work with, but after a while Dr. Itano and Dr. Singer and Dr. Wells were able to show that if they put a drop of hemoglobin solution from a patient with this disease in a little trough containing salt solution and applied an electric field putting electrodes into this trough, the hemoglobin from the sickle cell anemia patients would move in one direction in this trough and that from ordinary individuals would move in the other direction. This was the proof that these patients have a different kind of hemoglobin, they manufacture a special kind of hemoglobin molecule, which is the cause of their disease. This was the first molecular disease to be identified. That is, the first disease to be shown to be due to the manufacture by the patient of an abnormal molecule.
Transcript from Video Clip: Interview with Linus Pauling., Narrator asks how Pauling got interested in sickle cell anemia and they discuss antibodies, Landsteiner, molecular disease, stickiness and clamping, Castle, Itano, Singer, Wells, and reactions to finding the first molecular disease., 1960.

Narrator: Dr. Pauling, in the last few years you have become interested in the biochemical basis of medicine, mental disease, and so on. Could you tell us what led you into this new work?Dr. Pauling: Well, I think that it was the discovery of sickle cell anemia as a molecular disease that has led to our present activities on the chemical basis of mental disease. You see, nobody had thought before that there could be abnormal molecules of proteins and that they could be responsible for disease. Genetic diseases have been known. You know that each human being has about, let's say, a hundred thousand genes that he has inherited from his father and mother. Half from his father and half from the mother. These genes are now known to be molecules of a substance called deoxyribonucleic acid and each of these molecules has a little code of information on it that permits it to manufacture duplicates of itself to be handed on for example, to one's children, and also to manufacture special molecules such as the molecules of proteins, in which each atom is put in its right place in this product molecule. Each of these genes sets up an assembly line for manufacturing protein molecules. When we began studying hemoglobin -- the abnormal hemoglobin that produces sickle cell anemia -- we found a very interesting result. The hemoglobin in the apparatus in which an electric field operates on the hemoglobin molecules and pulls normal hemoglobin molecules to one side and the sickle cell anemia hemoglobin molecules to the other side. We found that if we got a sample of blood from the father or the mother of a parent, of the patient, and put the hemoglobin of the father in the apparatus it split. Half the molecules went one direction and half went the other. And similarly with the hemoglobin from the mother. Both the father and the mother had in their red cells a mixture -- a fifty-fifty mixture of two kinds of hemoglobin. Now the explanation of that is simple. A normal individual inherits two molecules of deoxyribonucleic acid, two genes, each of which manufactures normal hemoglobin molecules. A sickle cell anemia patient has two abnormal genes, that are somewhat different. Each of these manufactures molecules of sickle cell anemia hemoglobin. The parents of this patient have one normal gene and one abnormal gene. Each of these genes sets up its own assembly line and manufactures its own kind of hemoglobin molecules. The abnormal gene was presumably made by a normal gene many thousands of years ago probably by a cosmic ray or some other kind of high energy radiation or some other mutagenic agent, which damaged the gene in such a way it made only a small damaged region in it in such a way as to convert it into the sickle cell gene. This caused the sickle cell gene manufactures a hemoglobin molecule that is almost exactly right, but it has two little errors in it. Out of six hundred units that make up the molecule, two have been changed. And that is all the difference that there is between normal hemoglobin and sickle cell anemia hemoglobin. Now here we have the normal gene and the abnormal gene, the good gene and the bad gene. The bad gene was formed by a mutation, a genetic mutation, some thousands of years ago. It has spread out so that there are now millions of people in the world who carry this particular bad gene. We know that geneticists have discovered that human beings carry a great number of different bad genes and my associates and I have been especially interested in checking up on the bad molecules of proteins that the bad genes manufacture. In particular, in investigating these bad molecules in relation to disease.
Transcript from Video Clip: Interview with Linus Pauling., Narrator asks about mental disease. Pauling mentions sickle cell anemia got him into a new field, genetics of diseases, bad and good genes., 1960.

Narrator: Well, what are the broader implications of this concept of yours of molecular disease? Do you envisage, for example, a kind of new medicine which will be based more fundamentally on chemotherapy for example?Dr. Pauling: Yes, I would say so. I think that we shall be able to get a more thorough understanding of the nature of disease in general by investigating the molecules that make up the human body including the abnormal molecules and that this understanding will permit disease to be attacked, the problem of disease to be attacked, in a more straight-forward manner, such that new methods of therapy will be developed. For example, we are working now on a disease called phenylketonuria. Phenylketonuria is a disease that involves a bad gene. Normal human beings have inherited two genes from their parents that manufacture an enzyme, a special protein in the liver that catalyzes the oxidation of an amino acid, phenylalanine, to form another amino acid, tyrosine. Now, we ingest, we eat food containing phenylalanine all the time. An ordinary protein is about five percent phenylalanine. So that everybody gets a lot of phenylalanine into his body by way of eating proteon. He has to eat protein to build up his body. This phenylalanine is in large part converted into another substance by the action of the enzyme in the liver. One person in eighty has only one good gene for this enzyme and then he has one bad gene, the result of a genetic mutation. A bad gene that will not manufacture a good enzyme. These people, we have been studying the activity of the liver of these people. We give them some phenylalanine, and then we take a sample of blood and determine what has happened to that phenylalanine in the course of one or two or three hours, and we find that normal individuals are able to destroy, to change the phenylalanine to tyrosine twice as fast as these people, one in eighty, who are the carriers of one bad gene.
Transcript from Video Clip: Interview with Linus Pauling., Narrator asks, “What are the broader applications of molecular diseases?” Pauling replies that a better general understanding can be gained from this knowledge. They can now move in a straight-forward manner to attack therapy for disease. Also discusses phenylketonuria and his studies., 1960.

Narrator: I believe there are about two million mental defectives in the United States, and this would account for about twenty-thousand patients having this disease. But are you implying that you could conceivably inject a catalyst into one of these phenylketonurics and have them oxidize phenylalanine to tyrosine.Dr. Pauling: Well, I am implying this. Two or three years ago I gave the Edsel Ford lecture in Detroit. It was about the future of enzyme chemistry. And in this lecture I said, if I look forward, attempt to look forward fifty years or even twenty-five years, no fifty years is what I was talking about. Fifty years from now I think it may well be that we shall be treating patients with phenylketonuria -- children who, infants who are born with this disease, which can be recognized shortly after birth. We shall be treating them by sewing into a blood vessel a little capsule, open-ended tube, containing a synthetic enzyme that will carry out the chemical reaction that they are not able to carry out naturally because of their hereditary defect, due to the gene mutation. Yes, I think this is the sort of progress that will be made in medicine.
Transcript from Video Clip: Interview with Linus Pauling., Pauling mentions giving the Edsel Ford Lecture and his statements about the “Future of Enzyme Research.”, 1960.

Dr. Pauling: I hope that in a few years, ten years or twenty years, that we'll be able to say eighty percent of the mentally defective children who come into the world have an understood disease, and there's the possibility, since we understand the nature of the disease, that we can take some action that will cut down the number of children born mentally defective in the future.Narrator: And after ten or twenty years, what then?Dr. Pauling: Well, this is rather hard. I think that we are raising problems for the human race to solve. Medical research does raise problems, but the first step, of course, is to understand the problem, then you can work for its solution. Suppose that we take phenylketonuria: one percent of the institutionalized mentally defectives have this disease. We are working on a test that will enable us to say whether an individual human being carries the gene for phenylketolnuria or not. If this test is carried out then the person will know that he must be careful about marrying another person who carries that gene. If he does marry a second person who carries that gene, a quarter of their children on the average will be mentally defective. Well, suppose that we know that. What should he do? Should he refrain from having children, if two people are married and know that a quarter of their children will be mentally defective? At the present time the situation is that parents of a fellow phenylketonuric child can be told that the chance is twenty-five percent that any successive child they have will similarly be mentally defective. And so I ask, do they not have an obligation to refrain from having additional children? The pool of human germ plasm is deteriorating now. We can see it in the case of the disease involving sugar in the blood that's treated with insulin. There are more and more diabetics being born in the world. The incidence of diabetes has increased because of the discovery of insulin. As medical progress is made we enable defective human beings who carry bad genes to live a good life and to have children and to pass the bad genes on to their children. Normally the bad genes exist in the pool of human germ plasm in a certain number. New ones are formed all the time by cosmic rays and natural radioactivity and medical x-rays and fallout, radioactive fallout now. But some are being removed from the pool of human germ plasm through the death of the carriers without progeny. Medical practice, medical discoveries, medical progress now enables these defective individuals, the carriers, to live a better life, a happier life and to have children. Well, that means that the pool of human germ plasm is deteriorating. More and more bad genes are piling up in the pool of human germ plasm. Our work, I'm sure, will lead to similar medical progress and to the possibility of further deterioration in the pool of human germ plasm, in the nature of the human race, unless something is done about it. I think that something needs to be done about it. I think that society has to attack this problem. That sooner or later we must find a way of removing the bad genes from the pool of human germ plasm by some method other than the birth of defective children, who lead a life of misery and suffering and are unable to have progeny. That is not the humane way to purify the pool of human germ plasm, but it's a very dificult problem. Hitler had ideas about purifying the pool of human germ plasm, which are of course to be rejected. They are wrong. So this is a very difficult problem, which now society will have to face.Narrator: But don't you think there's a threat such as Huxley foresaw in "Brave New World," that we will attempt to control the intellectual and moral character of man by manipulating the physical basis of life?Dr. Pauling: Well, I think that for the foreseeable future, and this is probably thousands of years rather than just a few years. Our control of the nature of man, as determined by his heredity, will be such an incomplete one that we have nothing to fear. I think that the genes that are most deleterious, that produce the diseases, that cause the suffering that I've been talking about, are not intimately intertwined with other aspects of the character of human beings. So that I believe that we can take steps to remove these deleterious genes from the pool of human germ plasm that will not interfere in the slightest with the moral and intellectual character of human beings and emotional character of human beings.
Transcript from Video Clip: Interview with Linus Pauling., Marriage and children, what’s the parent’s obligation? Pauling discusses germ plasm deterioration, mutagenic effects caused by X-rays and radiation. He believes that society must attack this problem. Narrator asks about Aldous Huxley’s Brave New World, to which Pauling replies that he thinks the bad genes can be dealt with without changing other aspects of people., 1960.

Narrator: Now Dr. Pauling, quite aside from this very detailed and broad scientific career, you have always been a very outspoken person, and in the atmosphere of the United States you have been a dissenter and a non-conformist, particularly applied to this question of radiation hazards and fallout. Do you believe that this is a legitimate aspect of your work as a scientist that it falls within the domain of science?Dr. Pauling: Oh yes, I think that it is important that scientists do their duty as citizens. I think, in fact, that scientists have a greater obligation to formulate and express opinions about the social and political matters in the modern world than non-scientists. The modern world is what it is in considerable part because of the discoveries made by scientists. It is the scientists who understand these aspects of the modern world best and because they understand it, their opinions have special significance. I do not believe that scientists should just stay in their laboratories, do what they are told, and speak only when they are spoken to. I think that scientists need to take a part in the life of the community, the life of the world. And especially to work along social and political lines.
Transcript from Video Clip: Interview with Linus Pauling., Pauling states that scientists have a greater obligation than non-scientists to discuss the moral implications of their work and to work along social and political lines., 1960.

It occurred to me that the same magnetic methods that we had been using to study simple compounds of iron, in order to determine the bond type, could be used to study the hemoglobin molecule. One of my students, Charles Coryell, and I, then got some blood, cattle blood, and put it into an apparatus. It consisted of a balance, which we had fitted out in such a way that a wire was suspended from one arm of the balance through a hole in the base of the cabinet, and held a tube. This tube was placed between the poles of an electromagnet. We filled it with blood, oxygenated blood, and balanced it to measure its weight. Then we passed an electric current through the coils of wire and the apparent weight changed. It turned out that the blood was being repelled from the magnet. When we removed the oxygen molecules from the blood to get venous blood, the sort that flows through the veins in the body after it has given up the oxygen in the tissues, then we found that the blood was attracted by the magnet, attracted into the magnetic field. The iron atom had changed the nature of its bonds with the surrounding atoms. This led to an understanding of the nature of the structure of hemoglobin in the immediate neighborhood of each of the four iron atoms.
Transcript from Video Clip: The Life and the Structure of Hemoglobin., Magnetic test of cow hemoglobin done by Pauling and Charles Coryell. They used an apparatus with a balance and passed electric current through the blood to further determine the structure of hemoglobin., 1976.

Narrator: Along with his protein study, he had also been spending years looking into the properties of hemoglobin, in blood cells. Normal blood cells like these, are disc shaped, which enable them to pass through blood vessels easily. But blood cells can be diseased. Sickle cell anemia results with the sickling of cells, so that they become ridged, and crescent-shaped. The sickled cells clump together, making it more difficult for them to pass through the blood vessels. The disease is inherited, and often causes pain and weakness in its victims.Pauling: I had the idea in 1945 that the disease sickle cell anemia might be the disease of the hemoglobin molecule. No one had ever, so far as I'm aware, no one had ever suggested the idea of a molecular disease before. As soon as I had this idea I thought this must be right, from what I know of the properties of these patients. I believe that this is a disease of the molecule, and that if we look at the blood of these patients, we shall find that the hemoglobin molecules are different from those of other people.Narrator: Pauling had made a profound educated guess. But it took years before techniques were developed that could investigate his ideas. Eventually it was confirmed that the victims inherited hemoglobin, which does indeed have a defective molecular structure. Dr. Harvey Itano, who began working with Pauling in 1946, is today, along with other scientists, experimenting with different chemicals, trying to stop blood cells from sickling. Pauling has taught a generation of scientists to think in molecular terms, and he helped to establish the new science of molecular biology.
Transcript from Video Clip: NOVA: Linus Pauling, Crusading Scientist., Pauling talks about his work on hemoglobin and his realization of sickle cell anemia as a molecular disease., 1977.

I began to think about the substances that are present in the human body. For example hemoglobin, which is the striking one because of its color. The blood constitutes seven percent of a person's weight, and the hemoglobin is a seventh of the blood. So about one percent of your weight is hemoglobin. It's possible to get this substance rather easily -- just get someone and bleed him. I began doing a little thinking. I didn't know much, I'd had one elementary course in organic chemistry and no biochemistry. Didn't know much about these things. I was getting support from the Rockefeller Foundation. Warren Weaver said to me, "Well it's alright. We've been giving you some money to determine the structure of the sulfide minerals. But the Rockefeller Foundation isn't really interested in the sulfide minerals. We're interested in biological molecules and life." So I said, "Well, I'd like to study the magnetic properties of hemoglobin and see whether the oxygen molecule loses its paramagnetism when it combines with the hemoglobin molecule." So they said, "Alright, we'll give you more money."
Transcript from Video Clip: Origins of Molecular Biology and Molecular Medicine., Pauling talks about his thoughts on hemoglobin and his communication with the Rockefeller Institute regarding further financial support for looking into the magnetic properties of hemoglobin., May 20, 1986.

So I became interested in proteins. In 1936 we published this material. That year also I asked Alfred Mirsky to come from the Rockefeller Institute to Pasadena for a couple of years in fact. He taught me how to handle proteins, how to purify hemoglobin and things of that sort. He and I published a paper in 1936 on a theory of native and denatured proteins, which is, I think, pretty much the accepted theory -- that the native protein is folded in a well-defined way. This native protein molecule such as this one [slide] stabilized by various interactions including hydrogen bonds. And that denaturing agents are conditions caused polypeptide chains to unfold and they can get tangled up with one another and an insoluble coagulum can form. The denatured protein, the specific properties, tend to be lost. So I thought an interesting problem would be to find how the polypeptide chains are folded in proteins.
Transcript from Video Clip: Origins of Molecular Biology and Molecular Medicine., Pauling describes his work with Alfred Mirsky on the handling of proteins, the purification of hemoglobin and later their paper which outlined native and denatured proteins., May 20, 1986.

Well, I gave a lecture, Grand Rounds, at Rockefeller Institute for Medical Research in 1936. One of the people in my lecture was Karl Landsteiner. He had discovered the blood groups in 1900. He asked if I would come to his laboratory to talk with him, which I did. And later when I was lecturing at Cornell, he came up to Cornell, to Ithaca, for a week and gave me an intensive course, one of the best courses probably anyone ever got, in immunology, immunochemistry. So he asked if I could explain his observations on direction of apoproteins with analogous antiserum. And I didn't know anything about immunology and couldn't explain. But I began thinking and after four years, formulated my ideas. There were, at that time, two general ideas about how biological substances can show specificity. Enzymes, antibodies, the gene producing replicates of itself and so on. One is the idea that in some way, the molecule produces a replicate of itself. The other idea about biological specificity was the lock and key idea. In 1940, I published a paper on the structure of antibodies and the nature of serological reactions.
Transcript from Video Clip: Origins of Molecular Biology and Molecular Medicine., Pauling recalls meeting Karl Landsteiner, who discovered the blood groups, at Cornell and receiving an intensive course in immunochemistry from him. He then talks about how this influenced his understanding and his own ideas., May 20, 1986.

Well now I'll go on to sickle cell anemia, which was a pretty interesting matter. Here's a patient with sickle cell anemia. Here is an illustration from our paper in 1949, "Sickle Cell Anemia: A Molecular Disease." In 1945, when I heard about sickle cell anemia from Bill Castle, I wasn't very much interested. Anything involoving cells seemed to me to be far too complicated to have much interest for me -- at any rate the cell is such a complicated structure. But then when he said these cells are sickled, deformed in the venous blood and regain their normal shape in the arterial blood, I thought it must be that this is a disease of the hemoglobin molecule. After all, a red cell consists mainly of hemoglobin molecules, a hundred million of them per cell. And why shouldn't a hemoglobin molecule be something like an antibody to itself? Having two mutually complimentary combining regions on opposite sides, so that one molecule would clamp on to the next, and so on, building long rods which would line up side-by-side to make a needle-shaped crystal which as it grew longer and longer, longer than the diameter of the red cell, it would twist it out of shape. And an oxygen molecule that is stuck on to the hemoglobin molecule would be a large bump sticking out that would keep these combining regions from getting close enough together for this crystallization to occur. And accordingly the sickling would be reversed on oxygenation.
Transcript from Video Clip: Origins of Molecular Biology and Molecular Medicine., Pauling talks about first talking about sickle cell anemia with Bill Castle and his initial reactions., May 20, 1986.

He [Harvey Itano] tried a number of tests. The two hemoglobins seemed to be the same -- oxygen equilibrium curve and spectrum. But here, unless you get a difference, it's just a surmise that they are the same. When you don't observe a difference there may be a difference, as Professor Dickinson was pointing out to me in 1922, there may be a difference. So, our problem was that you couldn't buy a Tiselius apparatus. So we started building one, and it was quite a job. We had to have a big room because it was about 30 feet long tube, 30 feet long. It took a couple of years to get this apparatus built. Here we have the results. [slide] Normal hemoglobin at pH 7 moved toward the anode sickle cell anemia hemoglobin and the hemoglobin from a sickle cell anemia patient moved towards the cathode. And the mixture of the two was split. We mixed these two bloods, here, blood from either the father or the mother of the sickle cell patient came out like this. Two kinds of hemoglobin. They were heterozygotes. This hadn't been recognized, that this was a genetic disease of that sort where the manifestations of the disease showed up in the homozygote. So that led to a lot of progress. Dr. Harvey Itano and his other people in the laboratory found hemoglobin C and hemoglobin D and hemoglobin E. Schroder and I reported that there are two kinds of polypeptides chains in the hemoglobin molecules, two alpha chains and two beta chains. Other people began finding abnormal hemoglobins. The field of the hemoglobinopathies was built up. I think there are more than two hundred kinds of human hemoglobin that have been reported so far.
Transcript from Video Clip: Origins of Molecular Biology and Molecular Medicine., Pauling talks about working with Harvey Itano on testing different kinds of hemoglobin to observe their differences. Also discusses the number of different human hemoglobins reported so far., May 20, 1986.

I had a man come from Paris to work with me presumably for a short while on the oxidation reactions in marine organisms. But I asked him if he would get some hemoglobins, some blood from different species and run these protein patterns. This was before the days of amino acid sequences. And human, fish, lungfish, echiurid worm, shark. It's obvious that the hemoglobins are much different. Here, human, cow, pig, they're beginning to be more similar. In fact, when it became possible to determine amino acid compositions or sequences, it turns out that the difference between human and cow in the alpha chain is about 20 residues out of the 140. So you're getting close. Here we have human, chimpanzee, gorilla, orangutan, rhesus monkey. Well there are about 6 residues difference between rhesus monkey and humans, and about 1 residue between the alpha chain or beta chain in the chimpanzee. In fact, one of the chains is identical. So this is a way of setting up an evolutionary chart. Dr. Emile Zuckerkandl and I wrote a paper in 1962 on this subject. This was the start of molecular evolution. He is the editor, has been for 15 years of its existence, of the Journal of Molecular Evolution, Emile Zuckerkandl. Here back 20 years ago a number of differences. We started with horse and human, and put down 80 million - that's high, it should be about 60 million years - between the separation of horse and human probably. And horse and rhesus monkeys, their 6 differences, if you take this proportionality and say that there's one evolutionarily effective mutation every 4 million years, from 20 to 80, then the 6 [differences] would mean that human beings separated from rhesus monkeys 24 million years ago. Gorilla and chimpanzee it's 2 or 1 or 0 [differences], average would be about 4 million years, for the time when we separated from those anthropoid [?] apes. This evolutionary clock seems to be reasonably good. You have, I don't whether I have, oh yes, here's the slide, this is for Cytochrome-C, has about 100 or 105 amino acid residues in the polypeptide chain. Man and rhesus monkey only one. I haven't seen that anyone has studied man and the anthropoid apes, but probably there is no difference. One instead of 6 here, man and other mammals about 8 instead of 20, man and the birds about 14, man and tuna fish 21, man and the moth 30, man and baker's yeast 45. So in 60 of the positions, human beings and baker's yeast are analogous. We're moderately closely related to baker's yeast. Somewhat more closely related to the moths, and still more to tuna fish, and almost identical with the anthropoid apes.
Transcript from Video Clip: Origins of Molecular Biology and Molecular Medicine., Work with Emile Zuckerkandl who ran protein patterns of hemoglobin of different species. Also talks about the evolutionary molecular clock., May 20, 1986.

Well, orthomolecular medicine. I got interested in orthomolecular medicine -- I invented the word "orthomolecular" -- because I had been working on schizophrenia. When Harvey Itano left me to go back to Bethesda after eight years, I thought I don't want to compete with him, in studying the hemoglobinopathies. So I'll look at some other diseases and I decided on mental disease. I got some grants over a ten-year period and with my associates worked on mental illness.
Transcript from Video Clip: Origins of Molecular Biology and Molecular Medicine., Pauling talks about defining orthomolecular medicine and then states his new direction to avoid directly competing with Harvey Itano., May 20, 1986.

Various substances are normally present in the human body and many of them required for life and characterized by low toxicity. I call them orthomolecular substances. Here we have what the Food and Nutrition Board does, estimating the amount, the intake, needed to keep you from dying. That's the RDA. But you can also ask the question, "What is the intake that will put you in the best of health? And be most effective against disease." And when I went through the medical, nutritional literature to find out what this intake was I found there was nothing in the literature about it. Practically nothing, just a few papers had been written on this subject. Well, how do you find out? It's a little hard, when people ask me I say, "If you still catch colds you're not taking enough vitamin C." That's one way of finding out. It's interesting that for most vitamins, all animals require the substances exogenously. With little doubt what happened was, 600 million years ago, primitive animal was running around eating plants, his ancestors, these plants. His biochemistry was very much like theirs. Here he was able to synthesize thiamine and riboflavin and peroxygen and vitamin A. But he was eating the plants which synthesized them and he was getting enough in his foods so that he really didn't need this apparatus and he lost it. And ever since then, all animals have required these various vitamins. This didn't happen with vitamin C. And why not? Presumably because there isn't enough vitamin C in the foods. And one reason that animals require more vitamin C than plants is that animals have collagen as their principal macromolecular molecule, structural molecule, and plants use a carbohydrate, polysaccharide cellulose. So human beings can't synthesize collagen without using up vitamin C. They need more vitamin C than animals do so they've kept on synthesizing it. Unfortunately the common ancestor of all of the primates some 25 million years ago was living in a tropical valley where the food was so high in vitamin C that when a mutant came along that had lost the ability to make the enzyme that would produce vitamin C, he had an advantage over the wild type, and the wild type, and since then all the primates have had to get vitamin C exogenously. Most of them have had sense enough to stay in the tropics eating the foods that are high in vitamin C, but man has moved out into temperate and subarctic areas and has changed his eating habits in such a way that practically all human beings are suffering from a sort of subclinical scurvy, that is called "ordinary good health", but should be called "ordinary poor health." So we can ask, how much vitamin C do these animals manufacture? It's proportional to body weight. 70 kilograms of house flies manufacture 10 grams of vitamin C per day. In general, animals manufacture about 10 grams per day. It says here, 2 to 20 grams per day per 70 kilogram body weight. That's 40 to 400 times RDA for humans. I might as well mention now that I take 300 times RDA, 18 grams of vitamin C per day, and 80 times RDA of vitamin E and 25 times RDA of the B vitamins. Perhaps when I start getting old I'll go up to 50 times. 10 times RDA of vitamin A. It's interesting that the recommended amount of vitamin C is 70 times that for human beings. It's easy to understand that of course. Monkeys are expensive, probably $1000 each, I don't know, maybe $2000 each. If you've been spending the last year implanting electrodes in their brains and writing down things in a research book and then come in and the monkeys have died, that's a real tragedy. You can't publish a paper and you probably won't get tenure. So they've worked very hard to find out what the optimum intake of vitamin C is for monkeys.
Transcript from Video Clip: Origins of Molecular Biology and Molecular Medicine., Talk about appropriate amounts of vitamin C for humans and how due to evolution humans don't produce their own vitamin C., May 20, 1986.

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