Linus Pauling:

His Contributions to Chemistry and Molecular Biology.

Lecture by Pierre Laszlo (Ecole polytechnique and University of Liège) given at Southern University, Ashland, February 7 1998

Let me take you on a short walk. What's this? We ascend first a spiral staircase. It winds upward in highly regular manner, each step in the climb makes us circle a little around the axis of the structure. Thus, we come to a landing. We have reached a rather flat, but nevertheless undulating floor. We can move across it quite easily, till we reach another of the spiraling structures. The architecture I am describing is that of a building, neither man-made nor inhabitable. The building I'm telling you about is also the build-up of a protein molecule and its scale is that of atomic dimensions.

The man who made the first sighting of such an architecture for proteins, in the late 1940s, with its a-helices (the spiral structures) and with its undulating floors (the b-sheets) was Linus Pauling. His vision was, for that time, truly prophetic. And it has endured, it has been borne out by whole libraries of evidence accumulated since.

The two questions I wish to examine in this lecture are:

1. how did Pauling come to his notion of protein architecture?

2. were all the pronouncements by this visionary genius, those about vitamin C and cancer for instance, milestones in the advancement of science?

* * *

I'll start with the first question. We have a description from a witness of Pauling lying in bed in Oxford, England, and putting together cardboard models during a fertile period when he discovered how protein molecules were built. What kind of a trajectory did Pauling follow in-between his birth and early years in Oregon and the scene that I have just described and that took place in Oxford, when he was in his late 40s? In order to map it out for this lecture, I won't try to follow as if with a pin an itinerary on a road map, pointing out the intersections, here a turn and there a lull in travel, and elsewhere a temporary diversion or even a cul-de-sac, a road without an outlet. I shall go over that map with my finger, showing you only the gross outline of the route traveled.

The childhood first. Linus was the eldest son of a druggist, who died from a perforated stomach ulcer when the boy was 9. One month before his death, Pauling's father had sent a letter to a newspaper in Portland, The Oregonian, telling readers about his precocious nine-year-old son, who was such an avid reader, asking for advice about the proper books to give him.

As a teenager, Linus Pauling collected insects and minerals, in an orderly and thoughtful way. But a spectacular chemical experiment that he witnessed when he was 13 made him decide to become a chemist. In the meanwhile, Linus had decided for himself that God was an unnecessary idea and had become, in private, an atheist.

The next 10 years or so, leading to his marriage with Ava Helen when he was 22, are straight Americana, out of a biography of a Great American written for young readers. A parallel with Benjamin Franklin's Autobiography would not be far-fetched: Pauling continues to be extremely precocious; he makes up his own mind about everything; he supports himself through dire financial straits with menial unskilled jobs; and he has total disregard for any hierarchy and for authority that is not based on logic, or motivated by personal admiration.

The time of his marriage is not only that of his initiation into marital love and serenity, it sees also his initiation into x-ray crystallography. His mentor, Roscoe G. Dickinson, trained Pauling into following an established procedure from A to Z, that would unambiguously yield the atomic coordinates inside the unit cell of any crystal. And, just as a youngster he had been collecting mineral samples, he started collecting the structures of those minerals that he had determined with this brand-new x-ray methodology. He would also, a quarter of a century later, base his proposals fro protein structure on data that had been obtained using x-ray crystallography.

* * *

Here was one major difficulty though in applying X-ray crystallography to determining the structures of complex molecules, in that the direct, unambiguous approach became impractical and effectively forbidden. In Pauling's words, "for a crystal of even moderate complexity, such as an amino acid, the number of possible atomic arrangements provided by the theory of space groups is so great that the exhaustive consideration of them and elimination of all but one by use of the observed X-ray intensities cannot be carried out even with the aid of electronic calculating machines..."

There had to be another way to solve the structure. Pauling, when he was 27, discovered that he was able to do so with an educated guess. And it became for him a standard procedure for attacking scientific problems. He named it the "stochastic method". Here is a description, again in Pauling's own words: "The first step (...) is to make a hypothesis--a guess. The second step is to test the hypothesis, by some comparison with experiment. In general the test cannot be sufficiently thorough to provide rigorous proof that the hypothesis must be restrictive enough to make the hypothesis itself essentially unique; in other words, an investigator who makes use of this method should be allowed one guess. If he were allowed many guesses he would sooner or later make one that was not in disagreement with the limited number of test points, but there would then be little justification for accepting that guess as correct".

In the specific case of the problem of the structure of proteins, here is how Linus Pauling describes his discovery of the helical structural elements:
" day in March 1948, while I was at my home in Oxford (...) recuperating from a cold, I decided again to attack the problem of the configuration of polypeptide chains, for the first time in eleven years. It occurred to me to make a search for the simplest configurations--those in which all of the amino-acid residues are structurally equivalent. The most general operation that converts an asymmetric element in an identically equivalent element (...) is a rotation about an axis combined with a translation along the axis. The repetition of this general operation automatically leads to a helix. I attempted accordingly to find helical configurations of polypeptide chains involving planar amide groups with known dimensions, such that suitable hydrogen bonds were formed. Within an hour, with the aid of a pencil and a piece of paper, I had discovered a satisfactory helical structure".

We have here an account of scientific discovery formulated as problem-solving: could I solve first a simpler problem, said Pauling to himself, viz. can I predict the conformation of a homopolymer, a polypeptide made of a single aminoacid? This amounts to a space displacement that has to be an identity and that can occur only through a combination of translation and rotation. The problem is further constrained by both the planarity of the peptide bond, that links consecutive residues, and by the need to stabilize the structure with intramolecular hydrogen-bonds.

Linus Pauling was a wizard at this "stochastic method" that demanded, as he himself recognized, "that an investigator who strives to apply the method must have confidence in himself". Without belaboring the point, his utmost self-confidence could be abrasive to others: Pauling was self-righteous, he was given to oracular pronouncements and dogmatic statements, and he spent a great deal of time defending his published work against rival interpretations, including over minutia. He was the Pope to his own Church and, just like the Pope, he was infallible. However, and perhaps in contrast to the Pope, Linus Pauling had little use for Christian charity in questions of science. He invested considerable time and energy in finding errors in work by other investigators and he was very blunt in pointing out those errors, in private or publicly. There is one instance in which he totally destroyed the whole career of an otherwise an brilliant scientist, Dorothy Wrinch, who was also keen on elucidating the structure of proteins and whose theories Pauling ridiculed and made sure that she would be cut-off from funding by the Rockefeller Foundation. Pauling was infallible, he could not be faulted on anything, not even on the punctuation of his prose. There is an example of a paper (in American Scientist) that he withdrew, at the stage of the galley-proof, rather than having to discuss the location of a few commas or semi-colons with the editor!

But I have not came yet to the end of the answer to the first question, accounting for Pauling's discovery of the structure of proteins: how did he become interested in proteins in the first place, having started both in his intellectual curiosity and in his scientific career with minerals? Indeed, till 1935 and with the notable exception of his importation from Germany in 1930-1931 of the key ideas of the new quantum mechanics and of his devising their application to the question of how atoms get to form chemical bonds, Pauling was busy cranking out structures for all sorts of crystalline minerals, using the stochastic method. Thus, we shall remark in passing, he was accumulating quite a large store of empirical knowledge about the make-up of chemical matter.

Two events cooperated in 1935 to change the direction of Pauling's scientific investigations from the chemical to the biological. He could not get a grant renewed for his work on the structure of minerals using crystallographic techniques. Conversely, he let himself be convinced by Warren Weaver, of the Rockefeller Foundation, to start investigating biological phenomena by physico-chemical means. As Pauling himself put it : 'I simply followed the money". A mundane change for Dr. Pauling, but an epochal change for biology. It ushered in molecular biology which has became now a full-fledged scientific discipline in its own right. With his unabashed reductionist program, within the lineage of Claude Bernard, Louis Pasteur and Jacques Loeb, Pauling wrested out biological chemistry from the hands of the medical doctors into those of the chemical doctors. As a result, to quote just this one example, about a year ago the Department of Chemistry at Harvard University became the Department of Chemistry and Chemical Biology: such a name change was long overdue, 60 years after the start of the Revolution that Pauling performed. So far, I have presented to you the portrait of Linus Pauling as the scientist. We may want to call it Persona 1. It is that of someone who, at age 30, was already a world-famous scientist and had been hired as a full professor at Caltech and who had received comparable offers from Harvard and MIT. Indeed the photographs confirm our expectation for Persona 1: we see Pauling as a serious scientist, in a suit and a necktie. We notice that he is world-famous, many pictures show him on a podium, addressing a scientific conference or a lay audience; other pictures show him being interviewed by a journalist or doing a radio or a TV show. The culmination of this first series of pictures is of course that of Linus Pauling receiving the Nobel Prize in Chemistry from the King of Sweden in Stockholm in December 1954.

By 1954 however, Linus Pauling most of the time was acting-out an altogether different character, that of a political activist. Persona 2, as we may want to name it, was that of a public spokesman against fallout from nuclear tests in the atmosphere, in favor of nuclear disarmament and an advocate for peace. In the 1950s, Pauling had joined other luminaries such as Albert Einstein, J. Robert Oppenheimer, or Bertrand Russell in their very public and extremely controversial stand for the human race and against nuclear weapons. To many people in this country, Pauling had become, willy-nilly, a fellow traveler, someone who was blissfully unaware of the military threat from the Soviet Union and who was playing into the hands of the Communists. Indeed, he was investigated upon by organizations such as the FBI or the infamous Committee on Unamerican Activities. Whereas he had done secret work for his country during World War II and had a very high security classification, the crazy logic of the Cold War came to within an hair breadth of depriving Linus Pauling of his passport and thus of his right to travel freely all over the world. And this is obvious from pictures as well: this is no longer the actor in Persona 1, we see now a much more relaxed, a beaming Dr. Pauling letting himself be photographed in informal clothing. Persona 2 is that of the benign and smiling Grand-Dad who is busy making sure that Planet Earth wll be a better place for his grandchildren to enjoy.

But how did such a switch take place? Why did it happen? We are lucky to have this other story also in Pauling's own words. He calls it "An Episode that Changed My Life". This happened in 1945, shortly after the US dropped the two atomic bombs at Hiroshima and Nagasaki. Pauling had been asked by organization such as the Rotary Club in Hollywood to give lectures explaining, as a physical scientist, the principles of nuclear fission and the reasons why, because of the Einstein relation between mass and energy, nuclear energy was so huge. After the second such lecture, as Pauling and his wife had come home, she told him that she felt that his delivery was not up to his usual standards, because he had to rely upon work by other people and thus the talk lacked his usual mastery. Clearly, this cut to the bone. On the spot, Linus Pauling decided to devote himself whole he artedly, and at least for half of his time, to this goal of a peaceful world, "learning about international relations, international law, treaties, histories, the peace movement and other subjects relating to the whole question of how to abolish war from the world". As is well-known, Persona 2 culminated in the award of the Nobel Prize for Peace in 1962 by the Norwegian Parliament.

* * *

Persona 1 and Persona 2 already qualify Linus Pauling as a major historical figure of the Twentieth Century, as someone who ranks along (to quote but a few names) Marie Curie, J. Robert Oppenheimer and, of course, Albert Einstein. However, at age 60, nearing the usual age for retirement, our hero had still another card up his sleeve or rather, to resort to a similar metaphor as earlier on, he had in his hand yet another mask to put on. This was a character who had been standing in the wings, waiting to make his entry on the stage since the early 1940s. Let us welcome him: this is Mr. Pauling the maverick, wearing on his head at all times a black beret, as if to signal that he was distancing himself even more than he had done previously from the American mainstream. This is Mr. Pauling who is taking on the medical establishment and who claims that the solution to most health problems is to be found in better nutrition. This is the Pauling who advocates massive doses of vitamins E and C against ailments ranging from the common cold to cancer. And this is Professor Pauling turning all his skills as a scientific investigator into such an enterprise. What is going on here? Has he become senile? Is he being manipulated by unscrupulous people intent upon conning the public into buying their useless drugs, placebos at best? Why does Linus Pauling put his immense prestige on the line in support of what appears to most physicians to be quackery at its most dangerous, when it deludes terminal patients into avoidance of a serious and established treatment in favor of an unorthodox questionable reliance on mere vitamins? Pauling's Persona 3 is extremely ambiguous. He fancies himself as the pioneer of a new brand of medicine, for which he coins the adjective "orthomolecular", but the medical establishment is quick to marginalize him as at best an inoffensive buffoon. It is still a little early to answer in full these disturbing questions, except for one: how did Linus Pauling become interested, in the first place, in the relationship between disease and eating habits? The answer goes back to 1941. The news went though the grapevine of chemistry departments within the US like an electrical surge: Linus Pauling at Caltech was sick. He was seriously ill. He might be in danger of death. Would American chemistry lose in full strength, and in mid-career, its most prestigious and emblematic figure? The rumor was actually quite true. While Pauling was not on his death bed, he was indeed seriously sick. He was suffering from edema as a consequence of nephritis, of a kidney infection. Fortunately for Pauling, he met a Dr. Thomas Addis, a kidney specialist who held that healthy tissue, in the kidneys or in any other organ, was the expression of a dynamic equilibrium, of a balance between health and disease controlled by various parameters, such as the levels of various substances in the blood and in body fluids. Influenced by Addis, Pauling, instead of fighting his disease with the standard drugs, started paying attention to his diet, to the type of foods that he was ingesting. And indeed, only a few months afterwards, his health had improved significantly and the symptoms of his glomerulonephritis had receded, the edema in particular. He was able to resume his hectic pace of work and of lecturing and traveling. For the next few years, as Pauling continued to battle with his kidney ailment through improved eating habits, he became extremely conscious of the complex relationship of health with the concentrations of a number of molecules in various parts of the organism. As for the other questions, regarding vitamin C and cancer in particular, it is still too early to tell if Pauling was again a visionary and an inspired genius, or merely an irresponsible gadfly, or worse yet a dangerous charlatan in this Persona 3 garb.

* * *

Nearing the end of this presentation, I am aware that parsing a rich, full personality such as Pauling's into time-separated Personas 1, 2 and 3 is too arbitrary and rough a treatment . Of course, Dr. Pauling was all three persons more or less simultaneously. There are two reasons: (i) we know from the evidence of his notebooks that he attached himself to a problem literally for decades before he would come out publicly with a solution; (ii) he had the mental ability to meditate about quite a number of diverse topics simultaneously: for which there is the evidence of witnesses who, having knocked on his door, would Pauling find with his finger on the "Stop" buttoon of his Dictaphone machine. He would take the time to answer their question, whether in five seconds or in five minutes, before he would resume his dictation at the very point where in mid-sentence he had left it. We have also his own self-scrutiny: "as I read one sentence in Cannon's book," write Pauling, "I was conscious that I was thinking of a dozen other matters, of my lecture this evening, of a book by Courant and Hilbert that I couldn't find in my library, of the raising of funds to equip some labs in the new building, of the time of day, of the structure of an intermetallic compound--all within one or two seconds of time".

* * *

To sum-up: Linus Pauling ranks with a few other geniuses. He was most remarkable in his refusal to be cubby-holed in a niche of science, he had the ability to pick important problems to work on, ranging from nuclear structure to an explanation for anesthesia, and he exercised strong, patient application often for many years, till he would be able to come up with an explanation. The curiosity he had as a youngster for the natural world never left him. He had a strong belief in the power of rational argument, including in human and in political matters. There are several important themes I did not have the time to go into. One of them is that of Pauling the loner, a Dr. Know-It-All who had relatively little regard for fellow-scientist, who was literally peerless. One might argue that the lack of at true intellectual challenge from other scientists finally caught up with him during his Persona 3 period.