Dr. Manuel Varela – About Linus Pauling: The King of Vitamin C

Jun 11, 2017 by

An Interview with Dr. Manuel Varela – About Linus Pauling: The King of Vitamin C

Michael F. Shaughnessy –

1) Nobel Prize winner (if I am correct) and researcher par excellence, Linus Pauling was one of the giants of the past century. What do we know about his early life?

Linus Carl Pauling, a Laureate of two Nobel awards, was born on the 28th of February in 1901, in Portland, Oregon, in the U.S. He is considered by many to be one of the greatest scientists who has ever lived. His parents were Herman and Lucy Isabelle (nicknamed Belle) Pauling.

Unfortunately, his father, a druggist of modest means, died suddenly of a perforated ulcer in 1910, when Pauling was only nine years old, leaving behind a young widow and three children, two of whom were Pauling’s younger sisters, Pauline and Lucile.

During this time, Pauling’s mother, Belle, developed a chronic disease known as pernicious anemia, involving a deficiency in vitamin B12 and a consequent inability to produce red blood cells. Tragically Pauling’s mother was, at the age of 45, committed to an insane asylum, 16 years after her husband’s death. A few weeks after being committed, she died of influenza and pneumonia, conditions made to be worse apparently by her chronic pernicious anemia condition

In his youth, Pauling, a voracious reader and lover of brain teasers, was already considered to be precocious and brilliant. In fact, he was considered, in retrospect, to have been a genius. His interest in the field of chemistry, and later biochemistry, was influenced by a childhood friend, Lloyd Jeffress, who had built a homemade chemistry set. In particular, Pauling had been greatly interested in one of the experiments of the chemistry set, namely, the conversion of sugar to carbon, using a flame. They actually set sugar on fire! Pauling’s interest in carbon and later studies of carbon-containing compounds would prove to be of great importance in several of his early scientific discoveries.

When Pauling was a teenager, he came across an old abandoned and defunct metal smelter, with an accompanying old laboratory. Salvaging the old laboratory glassware, equipment, and left-over chemicals from the smelter, Pauling assembled a makeshift but rudimentary and surprisingly sophisticated laboratory, for a youth of that age, presumably in the basement of his house.

2) Where was he educated? (It always amazes me when a group of scholars all come from the same college or university)

Pauling entered Washington High School, in Portland, at the age of 12. Having then taken all of their relevant science courses, Pauling left high school early without having graduated, at the age of 16, in order to enroll at Oregon State University, called Oregon Agricultural College at the time, located in Corvallis, OR. As you indicated in your question, this institution has had many prominent alumni, Pauling among them. Studying chemistry in their main building named Science Hall, but known colloquially as the “Chem Shack” by students and faculty alike, Pauling took his degree in chemical engineering in 1922. During his senior year in college as an instructor of a course in chemistry for economics majors, one of his students, Ava Helen Miller, would later become his wife.

Turning down a graduate fellowship offer from Harvard, Pauling entered graduate school at the California Institute of Technology (Caltech) in Pasadena, California. This is another institution with prominent alumni, currently including as of this writing 34 Nobel laureates. After only three years in graduate school, and having already published 5 scientific papers, Pauling earned his doctorate, summa cum laude, in the field of chemistry while minoring in both physics and mathematics, in 1925.

Upon the advice of his Caltech doctoral advisor, Prof. Arthur A. Noyes, the newly minted Dr. Pauling turned down a postdoctoral fellowship offer from Berkeley so that he could accept another offer from the laboratory of Prof. Arnold Sommerfeld, at the prestigious Institute of Theoretical Physics, located in Munich, Germany. This higher educational institution also housed extant scientists and produced alumni who became giants in their respective fields. Pauling’s interactions and associations with these numerous investigators facilitated many later productive collaborations.

Just prior to his arrival at Munich in 1926 Pauling received a prestigious Guggenheim fellowship to conduct his postdoctoral research. While in Munich, Pauling was assigned by Sommerfeld the task of calculating the behavior of spinning electrons inherent in a model of the atom developed by Niels Bohr and modified by Sommerfeld—together constituting a so-called Bohr-Sommerfeld model of the atom. As an aside, the story is told that the neophyte Pauling approached Sommerfeld to point out that a paper, previously published by one of Sommerfeld’s Ph.D. students, contained an error in its mathematical treatment, which now meant that electron spinning around atoms was not as problematic as previously thought.

Pauling travelled throughout Europe visiting or working briefly in the laboratories of Niels Bohr in Copenhagen, Max Born in Göttingen, and Erwin Schrödinger in Zurich. During this sojourn, Pauling met many great and soon-to-be-great scientists, including Paul Dirac, Walter Heitler, Fritz London, and Robert Oppenheimer. Shortly after this, Pauling became a faculty member at Caltech, as an assistant professor in 1927 and becoming a full professor of chemistry in 1930.

3) Now, what was his first notable discovery?

While a Ph.D. graduate student at Caltech, Pauling’s very first scientific discovery involved the structural determination of molybdenite crystals, publishing this work in 1923. Rapidly acquiring an acumen in the technique of X-ray crystallography, Pauling determined the molecular structures of six additional chemical crystals in graduate school. Despite the presence of so many brilliant and prominent to researchers at such a world class institution, Pauling, nonetheless, stood out as being one of the most brilliant of their students at Caltech.

As a Guggenheim postdoctoral fellow and influenced by the works of Wolfgang Pauli and Erwin Schrödinger, Pauling acquired an expertise in the burgeoning field of quantum wave mechanics. He used his new wave mechanics tools to focus on the behavior of the outermost electrons that orbit larger atoms, and in so doing Pauling made what is considered by many in the field to be his first major and pioneering discovery of note. In greatly simplifying the mathematical approach to wave mechanics as applied to the electron behavior among the large atoms, others could then make significant advances for other elements and then on to even larger molecules. This work was published during 1927 in the prestigious Proceedings of the Royal Society of London.

Almost immediately after this publication Pauling then applied his quantum tools to predict the atomic sizes of ions by examining the behavior of electrons in their outer shells and how they were shielded by electrons in the lower atomic orbitals. These data helped to predict how ions would interact with each other when present in crystals. Publishing this newer work, also in 1927, Pauling solidified his reputation worldwide amongst physicists and chemists as a stellar investigator. Based on these works, others in the field could then combine X-ray crystallography with wave mechanics in order to test new ideas based on each area and to then make new advances in the chemistry of larger molecules, including biologically important ones.

4) What exactly is this alpha helix and what is its relevance to science, biology and chemistry?

The alpha (α) helix is a central structural motif present in proteins of all living organisms. The amino acids that make up protein molecules are arranged like pearls along a string that can form a spiral to make the α-helix structure. Using calculations of bond angles and turning the atoms in the amino acids around each other to make new theoretical hydrogen bonds along the protein chain, the α-helix structure came to Pauling during, the story is told, when he was laid up in bed with a cold—he quite frequently suffered from colds and secondary sinus infections. The theory for the α-helix structure was formulated by Pauling while convalescing.

The α-helix was a key piece of knowledge by which investigators astutely used in order to propose the structural model of DNA. Scientists James Watson, Francis Crick, Rosalind Franklin and even Linus Pauling himself applied the α-helix motif of protein chains to formulate the double helix and (inaccurately) the triple helix structural models of DNA.

Students of Biochemistry courses and especially Biochemistry undergraduate majors, are regularly taught all about the famous α-helix structure and its discovery. The hydrogen bonds and the peptide bond angles, their bond rotations, the side chain orientations, etc., in the α-helix are all classically taught in lectures and are unfailingly presented in any good Biochemistry textbook.

The α-helix is one of my favorite molecular structures; in fact, for my Ph.D. thesis, I studied a bacterial antimicrobial efflux pump that shared an evolutionarily conserved amino acid sequence motif; this particular sequence motif had an α-helix structure to it. I think it’s an elegant and beautiful structure.

The α-helix structure figures prominently in the inner workings of many proteins, perhaps, for example, by binding to key substrates in enzymes in order to catalyze biochemical reactions or by changing its protein configurations of transporter proteins during the uptake of nutrients by cells or by expelling toxic compounds (like antimicrobials) or waste products from cells. Virtually all biochemical and cellular functions involving proteins will have their molecular mechanisms carried out by protein structures composed of the α-helix.

5) I know that the British used to become ill on long ocean voyages until they began to eat limes, thus becoming known as “limeys,” and, of course, limes contain vitamin C. But how did Linus Pauling take this idea and link vitamin C to cancer prevention? (and I have to tell you, I am going to buy some more vitamin C on the way home today!)

The story of limes and of British sailors is an interesting one. Vitamin C, which is also referred to as ascorbic acid or ascorbate, is present in certain fruits, like limes, vegetables, and foods, like sauerkraut. These types of vitamin C-containing foods were indeed often brought along during prolonged sea voyages, in order to prevent a serious disease called scurvy. This condition is brought about by a deficiency in vitamin C.

The discoverer of vitamin C, Prof. Albert Szent-Györgyi, earned the Nobel Prize in Physiology or Medicine in 1937, for this work. Many animals still harbor the four-step biosynthetic pathway to make vitamin C. Such animals don’t require dietary vitamin C. In the course of our evolution, however, human beings have lost the fourth enzyme in the pathway that makes the vitamin C molecule. Hence, vitamin C must be supplied in our diets, and daily nutritionally balanced meals usually suffice in filling this bill. The current U.S. recommended daily allowance (RDA) of vitamin C in adult males is 90 mg while that in adult females is 75 mg.

Vitamin C is ‘vital’ because it plays a role, for instance, in our collagen producing machinery by allowing the amino acid proline to undergo biochemical processing to make 4-hydroxyproline during a reaction catalyzed by the enzyme prolyl hydroxylase, a member of the dioxygenase family of enzymes. Without this particularly helpful vitamin C, a person suffering from scurvy will experience a degeneration of their bones and connective tissues, resulting in the hemorrhaging of their blood vessel, loss of their teeth, slowed healing of their wounds, become prone to gum infections, and suffer heart failure. In mild cases of vitamin C deficiency, patients often experience severe tiredness, irritability, and enhanced frequency of infections in the respiratory tract.

Furthermore, vitamin C has been demonstrated to be an effective anti-oxidant, preventing damage to metabolic building blocks for DNA and protein biosyntheses. The biochemistry of the antioxidant property of vitamin C has been demonstrably worked out. Vitamin C has also been shown to be important for proper functioning of various components within the immune system.

Pauling’s interest in vitamin C began in 1965 with what one might call a ‘crank letter.’ Being a famous person worldwide for making so many discoveries in so many distinct areas of science and, especially, for having won the Nobel in Chemistry in 1954 and the Nobel Peace Prize in 1962, Pauling regularly received many letters of a somewhat dubious nature. The letter in particular was from an industrial brewing biochemist by the name of Irwin Stone. Pauling and Stone had previously met briefly during a ceremony honoring Pauling with the so-called Carl Neuberg Medal, an award for having made a significant contribution linking biological knowledge with that of medicine. In Stone’s letter, he reminded Pauling that at the ceremony he (Pauling) remarked that he would like to live 20 years longer in order to witness the new advances occurring in the sciences. Stone is recorded to have asked why only 20 years—why not 50 years longer?  Stone went on to say that vitamin C was the key. Stone maintained that just taking enough vitamin C to prevent scurvy was not sufficient for good health. Stone held that mega-doses of the vitamin helped him rapidly recover from severe injuries sustained during a serious car accident.

In retrospect, it is easy to see how Pauling was hooked, because he already had an interest and notion of the relative non-toxicity of the vitamins. From a psychiatrist friend, Pauling had learned about, for instance, the efficacy of niacin (a B vitamin) for mental disorders. Additionally, Pauling’s good friend, Prof. George Beadle, and 1958 Nobel laureate for his work on metabolic regulation by enzymes that are specified by genes, told Pauling about his work with mutants of his microbe, a fungus called Neurospora, which needed vitamins in order to grow.

Thus sufficiently encouraged, Pauling started taking daily mega-doses of vitamin C, on the order of 3 grams, many times the RDA value. According to Pauling, the benefits were immediate and remarkable. Straightaway, Pauling noticed that he had more energy, and, importantly, his frequent colds and their often accompanying sinus infections, a real nuisance for Pauling, had all ceased to occur. Thus, suitably converted, the mega-dose regimen was now part of Pauling’s daily routine. Yet, he did not publically advocate vitamin C till three years later, when he suggested its use for mental illness, a treatment he called ‘orthomolecular medicine,’ in which the most appropriate amounts of a missing substance, a substrate or enzyme co-factor, could be administered to patients, like insulin for diabetes, or fluorine for dental caries.

Pauling’s interest in cancer and vitamin C began in 1971 with another letter. This time it was from a physician, Ewan Cameron, who claimed that vitamin C at 10 grams daily was slowing tumor growth in his cancer patients. Since then, the issue of cancer prevention with daily mega-doses of vitamin C has been controversial. Many groups have reported success with cancer and vitamin C, and seemingly just as many others have reported no effect at all, with both proponents and opponents apparently deeply mired in a quagmire. One problem inherent in the issue is that cancer is a multitude of illnesses, depending on, for instance, the nature and extent of the affected cell, tissue, and organ. Also playing important factors are how early diagnoses are made, the level of natural resistance (immunity) of the patient, genetic pre-disposition or hereditary history, and among other factors how healthy a person may be, in general. One has the impression that it will be a very long time before the issue is clearly and finally settled.

6) What were some of his other discoveries and accomplishments?

In a word, Pauling’s important discoveries and accomplishments were plentiful. I shall briefly highlight only a few. Let’s first address the work for which he earned the Nobel Prize in Chemistry in 1954. The award was bestowed to Pauling for this studies on the so-called nature of the chemical bond and its uses in helping to determine the molecular structures of other important molecules, many of which contained carbon. Pauling had the astute realization that the chemical bonds between carbon and nitrogen atoms, called peptide bonds, were planar (flat) and that their carbon bond angles were tetrahedral (making 4 bonds) in nature—producing a structure appearing like that of the edges of a pyramid.

In addition to discovering the α-helix structure, Pauling also participated in the elucidation of the so-called beta (β)-strand nature of the polypeptide. When folded properly around themselves in a zig-zag type of conformation, the β-strands produced a so-called β-sheet structural motif. These works ultimately led to the elucidation of structures for other biologically important molecules, like hemoglobin and many proteins that are functionally important in the immune system.

Pauling also had an interest in determining the structure of DNA, but unfortunately he lost the ‘race’ to solve the structure first when he had inaccurately proposed a triple-helix model, instead of the correct double-helix molecule. Francis Crick and James Watson, who had accurately predicted the double helix structure, had also previously and inaccurately proposed a triple helix version themselves.

Interestingly, there is the popular story that at the time because of Pauling’s political leanings and activists movements, his passport was revoked, and, consequently, he was prevented from attending an important scientific conference in which he would have no doubt heard about the important X-ray crystallography data by Dr. Rosalind Franklin—the same data upon which Crick and Watson had used to produce their accurate double helix structure. In the story it is speculated that perhaps, if Pauling had only seen Franklin’s good X-ray data himself, he may have beat Watson and Crick to the correct double helix DNA structure.

While it is true that Pauling most certainly had political enemies, was intensely investigated by Hoover’s FBI and that his passport was denied, the other aspects of the story have been nonetheless refuted. For example, it is said that Pauling’s close collaborator Robert Corey did attend the conference and saw Franklin’s data. It is further said that Pauling was later able to retrieve his passport and visit the European laboratories at a later time—although it is recorded that Pauling did not visit Franklin’s laboratory. Pauling himself later remarked that his push to study DNA was not as much as had been anticipated by Watson and Crick.

Pauling’s contributions to the development of the fields of molecular biology and immunology are also significant. While collaborating with another famous scientist, Max Delbrück, early on they predicted that DNA synthesis, a process also called replication, occurred in a complementary way (i.e., complementarity). Similarly, Pauling had predicted that antibodies combined with their corresponding antigen molecules in a complementary fashion. In this way, the molecular structure of the antibody would be matched by the counterpart structure of the antigen in which they would correspondingly fit together in a precise molecular manner.

Pauling also had an interest in the inner workings of the active sites of enzymes, proteins which catalyze chemical reactions in their active sites producing new products but are themselves unchanged during the biochemical reactions. He showed that these enzymatic active sites are stabilized in order to mediate their chemistry activities. Additionally, Pauling formulated the notion that the debilitating disease called sickle-cell anemia could be due to an aberrant hemoglobin structure encoded by a defective gene. Pauling called this situation a molecular disease and started what is now known as molecular medicine within the overall field of molecular genetics.

Pauling and his wife are also noted for their extensive political anti-war and anti-nuclear activities. Their activist efforts where far-reaching and effective in influencing nuclear policy. In this regard, Pauling was awarded the Nobel Peace prize in 1962; he had regretted that Ava did not receive the prize along with him. Pauling is, nevertheless, in the rare situation of having earned two Nobel Prizes, each bestowed to a sole recipient, and each in different categories.

7) What have I neglected to ask?

Of the amazing scientists discussed in this series, Pauling is thus far the first of whom I have had the great opportunity and pleasure to see in person. Furthermore, the very second time I was in the same room with Linus Pauling he had a profound and irrevocable effect upon me.

When I was an undergraduate at the University of New Mexico in the 1980s, I attended an evening seminar given by Dr. Pauling. I remember that the largest auditorium on campus with just under 900 available seats was filled to capacity. After all of these years, all I can remember about the topic that night is that he spoke about a ‘three-electron bond’ which I had never heard about prior to, or since, then. In any case, even though he didn’t mention vitamin C at all, I was amazed, impressed, and deeply grateful that I had had the once-in-a-lifetime chance to hear the famous Prof. Linus Pauling speak.

The next day, in telling a good friend all about the great Linus Pauling and his fantastic evening seminar, I didn’t need much convincing to eagerly attend his next technical seminar, scheduled for that afternoon. Thinking we were “sneaking in” to the smaller and seemingly private chemistry seminar held that day to hear Pauling, we happily sat in on this seminar, too. We went early and sat in good seats. We were pleasantly surprised when no one kicked us out, so we stayed. This time the 100 plus seating capacity in the technical seminar room, adjacent to the large auditorium, was overfilled, with many sitting on the floor and people standing at the doorways. The next thing that happened during that seminar given by Pauling changed me forever.

About 15 or 20 minutes into Pauling’s presentation, a professor in the audience raised his hand to ask about vitamin C! Now mind you, the actual topic of the technical seminar is lost to memory, but I do know that it was NOT about vitamin C. In his response to the wayward question, Pauling casually mentioned his ‘Freshman Chemistry Textbook.’ Pauling said that every single thing he wrote in his book, he understood—there was a murmur amongst the professors and students alike in the room. I think that we were all probably astonished that one could understand every single thing in a thick textbook, especially a chemistry textbook! Being an undergraduate, I know I was.

But then he stated that many textbook writers include topics in their books that they themselves don’t understand but yet fully expect their readers to do so—he then added that many professors quite often lecture on topics for which they don’t understand either, just as much as they lecture on the topics they do understand.  It was at that very minute that I promised myself that if I were ever to become a professor that I, too, would teach only that which I understood myself. To this day, this is precisely how I teach.

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