Finding Resources for Basic Science and Medical Research

Linus Pauling, 1949

[Exploring Linus Pauling’s popular writings on the shape of post-war science, part 4 of 5.]

Our job ahead.” Chemical and Engineering News, January 1949

The onset of 1949 brought with it the beginning of Linus Pauling’s one-year term as president of the American Chemical Society, and Pauling’s article “Our job ahead” outlined the message that he wished to convey to the society. In it, Pauling specifically addressed the financial concerns being faced by the ACS as well as the scientific community at large.

The society’s problems centered on the need to manage operating costs and member remunerations in the midst of rising costs of living. More broadly though, Pauling saw for the society a responsibility to try to improve financial conditions for science as a whole. Pauling argued that the destruction of war, in tandem with the massive consumption of natural resources required by the war effort, had resulted in increasing levels of poverty throughout the world. Pauling encouraged the ACS to do its part to combat the problem by supporting and participating in global interdisciplinary scientific cooperation.

Pauling also pushed for ACS support of basic research, believing that work of this sort was most likely to lead to significant breakthroughs. Doing so would be made all the more effective by the creation of a National Science Foundation, which would issue and administer unrestricted grants on behalf of the federal government. It was Pauling’s ultimate vision that the majority of research dollars be provided by the federal government, with supplementary funding being made available by state governments, permanent endowments, private foundations, and industry.


Chemistry and the world of today.” Chemical and Engineering News, September 1949.

The themes put forth by Pauling in his initial message to the ACS – particularly the need for a National Science Foundation – were continued in his presidential address, delivered in fall 1949.

Pauling opened his talk with a broad question, “What can I say under the title ‘Chemistry and the World of Today?'” His answer was “that I can say anything, discuss any feature of modern life, because every aspect of the world today – even politics and international relations – is affected by chemistry.”

Pauling’s all-roads-lead-to-chemistry perspective informed his strong support of a potential National Science Foundation and his firm belief in the value of basic research. He lamented the ongoing struggle for funding faced by so many of his colleagues, and pressed the notion that even applied science was dependent on advances in basic science. Moreover, Pauling suggested that applied science often received the credit for ideas that had initially been discovered or cultivated by basic researchers.

Above all, Pauling believed that, in the post-war era, “…a nation’s strength will lie largely in the quality of its science and scientists.” That noted, Pauling emphasized that government funding for scientific research should not be funneled toward military channels. To this end, it was the responsibility of the ACS, as an organization representing American chemists, to make its voice heard in the fight for the creation of a National Science Foundation.

During Pauling’s presidential year, the concept of the NSF had been put forth in political circles but had not yet been acted upon. Looking forward to that day (which would, in fact, come the next year) Pauling put forth an ideal scenario where the NSF would fund $250 million a year in research, while science-dependent industries would fund an additional $75 million. Of this latter contribution, Pauling believed that private funding ought to be considered as a form of insurance rather than charity, since it was certain to fuel the scientific discoveries necessary to drive industrial development.


“Structural chemistry in relation to biology and medicine.” Second Bicentennial Science Lecture of the City College Chemistry Alumni Association, New York, December 7, 1949. Baskerville Chemical Journal, February 1950. 

At the end of 1949, Pauling gave another high profile public lecture, this time to the City College Chemistry Association in New York. In this talk, he focused on the relationships between structural chemistry, biochemistry, and molecular medicine.

Pauling began by citing the role that chemistry had played in catalyzing immense achievement in medicine over the preceding half-century, referencing in particular the discovery and refinement of chemotherapeutic agents including antibiotics. That said, Pauling was quick to point out that scientists still had a very poor understanding of the principles and structural attributes underlying chemotherapeutic functions. It was Pauling’s belief that “…if a detailed understanding of the molecular basis of chemotherapeutic activity were to be obtained, the advance of medicine would be greatly accelerated,” and that structural chemistry was fast approaching a point where it could produce this understanding. Once done, Pauling suggested that the decade or two that followed would surely offer significant advancements in the scientific understanding of medicine and the development of new pharmaceuticals.

Pauling then identified a collection of major areas where he thought biomedical research should be focused. The first involved developing a detailed molecular structure of 1) chemotherapeutic substances (i.e., antibiotics and other medications), 2) the organisms against which they are directed (bacteria, viruses, etc.), and 3) the human organism which they are meant to protect. A second major program of work should delve into the nature of the forces involved in the intermolecular interactions between the above substances and organisms.

Pauling pointed out that the last quarter century had seen great progress in the first goal – the science of organic chemistry had been developed and the structures of many organic compounds had been confirmed. But progress elsewhere, though promising, had not come about so quickly. For questions related to the physiology of disease-causing organisms and of the human body itself, advancements were fated to be slow simply due to the immensity of the task. In addition, structural chemistry was a fairly new field and, although it was growing quickly, the stock of previous discoveries upon which one might expand was finite (research thus far had mainly focused on the structures of amino acids and peptides).

The latter goal, an understanding of the intermolecular interactions between chemotherapeutic substances and the organisms they are meant to treat or defeat, had seen the least progress of all. It was a complicated task for sure, and though he had very little data in hand, Pauling offered a back of the envelope theory about what might be going on, speculating that

…some drugs operate by undergoing a chemical reaction with a constituent of the living organism, and that others operate by the formation of complexes involving only forces that are usually called intermolecular forces.

Regardless, Pauling felt that work in these areas would prove integral to the conduct of future medical research, and he put forth his own work on sickle cell anemia as an example of how other investigations might unfold. Specifically, Pauling and his team had discovered that the hemoglobin present in the red blood cells of afflicted individuals differed structurally from normal hemoglobin. Were other investigators able to develop a similar molecular understanding of a given disease, producing new treatments would be that much easier, since chemotherapeutic agents could be tailored to fit a particular molecular architecture. Work of this sort would

…represent the first time that a chemotherapeutic agent had been developed purely through the application of logical scientific argument, without the significant interference of the element of chance.

Similar to his call for an NSF, Pauling encouraged the creation of an institute for medical chemistry that would train a new generation of students to apply chemistry to medical problems. Doing so, in Pauling’s view, ought to be prioritized due to its potential significance to the health and happiness of all people.

Unsolved Problems and Hope for the Future

Lecturing on structural chemistry at the Richards Medal ceremony. Pauling received this award from the Northeastern Section of the American Chemical Society in 1947.

[Linus Pauling and the promise of post-war science, part 3 of 5.]

Unsolved problems of structural chemistry.” Acceptance address for the 1947 Theodore William Richards Medal, awarded by the Northeastern Section of the American Chemical Society. Chemical and Engineering News, October 1947.

In May 1947, Linus Pauling received yet another award from a chapter of the American Chemical Society. This time it was the Theodore William Richards Medal, granted by the Northeastern section of the ACS.

Pauling chose to use the occasion to speak on “Unsolved Problems of Structural Chemistry.” At the beginning of his talk, he praised the progress that had been made in the field over the previous twenty-five years, and then speculated on the potential for advancement over the next quarter century. In his address, he sorted the discipline’s “unsolved problems” into four categories: “comic-strip science,” “some puzzling small problems,” “some larger problems,” and “some great problems.”

Pauling’s “comic-strip science” designation referred to depictions of chemistry aimed at children as well as other popular-media portrayals, including magazine advertisements. Pauling believed that many young people were first introduced to the concepts of atoms and molecules through comics, a point of entry that was often capable of instilling a reasonable understanding of basic concepts. On the other hand, advertisements for household products often hinted at the chemical properties that made the products effective, but these details were usually under-explored and not well-understood. In particular, Pauling cited pin-point carbonation – an old-fashioned process by which bubbled were added to sodas, seltzers, and other beverages – and the activation of chlorophyll in household deodorizers as two examples of chemical reactions that were taken for granted in daily life but still not adequately explained by scientists.

By “puzzling small problems,” Pauling meant to refer to ongoing research on the molecular structure of simpler molecules, for which newer methods had begun to produce greater insights. His “larger problems” were also structural in nature, but more complex and theory-based, and primarily relating to the structures of groups of substances rather than individual molecules. This category also included studies on the extent to which covalent bonds between metal atoms occur in nonmetallic compounds. Pauling’s list of “great problems” included the structure of metals and intermetallic compounds, the structure of activated complexes, and an array of questions in organic and biological chemistry, especially the structures of proteins and genes, and the relation of structure to biological specificity.

Having provided an overview of these types of problems, Pauling concluded with optimistic rhetoric that was consistent with his talks of this time:

The progress of science in recent years is bringing biology and medicine into closer and closer contact with the basic sciences, and I am confident that the next few decades will bring to us a detailed understanding of the molecular structure of biological systems, and that this understanding will help in the rapid general progress of biology and medicine.  


“Chemical achievement and hope for the future.” Silliman Lecture presented at Yale University in October 1947, on the occasion of the Centennial of the Sheffield Scientific School. American Scientist, 1948. 

Pauling took a similar approach to his 1947 Silliman Lecture, delivered at Yale University in the fall. In thinking about “Chemical achievement and hope for the future,” Pauling began by examining the past century of scientific achievement in the field of chemistry. This period was one characterized by transition from “an empirical and descriptive science to an exact and theoretical one.”

For Pauling, a perfect example of this transition was the study of chemical thermodynamics, a field that had developed in conjunction with improvements in the understanding of molecular structure, among other fairly recent discoveries. Pauling also pointed out that, over the last hundred years, precise atomic weights had been assigned to most of the elements, and many of those predicted by sequences in Mendeleev’s periodic table had been discovered, along with the noble gases and a subset of man-made elements.

Pauling then summarized the last century of scientific achievement in each of the sub-fields of chemistry. For inorganic chemistry, he cited an increased understanding of the molecular structure of substances, particularly those needed to synthesize silicon-based substances that behave like carbon-based ones. These compounds included synthetic diamond and rubber, both of which were extremely useful to industry.

For organic chemistry, Pauling spoke to breakthroughs in both the “art of organic chemistry” and a corresponding but previously distinct “science of organic chemistry,” and identified as the greatest achievement in the field the unification of the two. The ability to synthesize new plastics was one major tangible outcome that arose from this consolidation within the discipline.

In Pauling’s view though, the field in which the most significant breakthroughs had occurred was clearly biomedical chemistry. Over the past five decades, average life expectancy had risen some sixteen years and childhood mortality rates had plummeted by 90% in the last twenty-five years alone. Numerous maladies had been controlled or nearly eradicated, though threats in the form of polio and flu viruses remained; so too degenerative diseases like cancer and heart disease.

As he considered the possibility of future advancement in medicine, Pauling emphasized the need for research on the structural basis of physiological activity, which he considered to be the greatest problem in chemistry. Work in this area was sure to reveal new insights into the behavior of antigens, proteins, enzymes, and other immunochemical actors, with medical progress emerging quickly from there.

Pauling wound up his talk with a look ahead. In so doing, he put forth the tantalizing idea that

This discussion has been confined to the least interesting aspects of the developments of chemistry in the future…those that can be predicted, that can be foreseen on the basis of our present knowledge…The great discoveries of the future – those that will make the world different from the present world – are the discoveries that no one has yet thought about…

Inspired by Walt Whitman’s “As I lay with my head in your lap, Camerado” Pauling confessed that he knew not where the future would lead but urged science to confront it head on. “Science cannot be stopped,” he implored,

Man will gather knowledge no matter what the consequences – and we cannot predict what they will be… 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.

Molecular Architects, Atomic Blueprints and Medical Progress

The Gibbs Award dinner, June 1946

[An exploration of Linus Pauling’s popular rhetoric on the potential for science following World War II. This is part 2 of 5.]

Modern structural chemistry.” [Acceptance speech for the Willard Gibbs Medal, awarded June 14, 1946 by the Chicago Section of the American Chemical Society] Chemical and Engineering News, July 1946.

In 1946, Linus Pauling was awarded the prestigious Willard Gibbs Medal by the Chicago section of the American Chemical Society for his work in structural chemistry. In thinking about his acceptance speech, Pauling ultimately chose to frame it as an overview of the history of modern structural chemistry.

Pauling began his talk with Lucretius who, in the first century BCE, began thinking about the properties of matter. Lucretius hypothesized that honey was made up of “smooth, round molecules which roll easily over the tongue, whereas wormwood and biting centaury consist of molecules which are hooked and sharp.” From there, Pauling rolled through the work of more contemporary greats including Lomonosov’s explanations of the properties of molecules in solid, liquid, and gaseous states; Dalton’s work on the weight relations of chemical reactions; and Avogadro and Cannizarro’s breakthroughs on chemical bonds.

Next up in the whirlwind tour were Frankland, Couper, and Kekulé’s theory of valence; Kekulé’s subsequent writings on the structure of the benzene molecule; and van’t Hoff and le Bel’s explanation of the right and left-handedness of substances. Rounding out the history lesson were Werner’s work on the spatial arrangement of chemical bonds, and Lewis’ identification of the chemical bond as a pair of electrons shared between two atoms. One outcome of all of these advancements was that the discipline of structural chemistry had moved firmly in the direction of the quantitative as opposed to the qualitative judgments that had permeated Lucretius’ analyses of taste and mouth-feel.

Pauling then noted that some of the most exciting and important developments in the history of modern structural chemistry had occurred during his lifetime. It was, for example, only during the early years of his career that methods for accurately measuring interatomic distances had been developed. Subsequent breakthroughs in methodology had included molecular spectroscopy, x-ray and electron diffraction, and applied quantum mechanics, among others techniques. More recently, new knowledge had been produced about moments of inertia, oscillational frequencies, the elucidation of molecular structures for specific substances including sex hormones and vitamin D, and the discovery of the β-lactam configuration of penicillin. In surveying this work, Pauling was particularly quick to praise the usefulness of x-ray diffraction as a powerful tool.

As he looked ahead, Pauling expressed a belief that the most promising application of modern structural chemistry would be its ability to explain the physiological activity of chemical substances. Previous research in this area had produced few results of importance, but Pauling felt sure that the structures of numerous molecules would soon be elucidated, thus laying the groundwork for new insights into physiological activity and, eventually, medical research on diseases like cancer and cardiovascular illness.  


Molecular Architecture and Medical Progress.” Radio talk broadcast on the New York Philharmonic-Symphony Radio Program and sponsored by the U. S. Rubber Company, October 13, 1946.

The ideas expressed by Pauling in Chicago were taken up again in this radio broadcast, which Pauling used to further explore the relationship between molecular structure and physiological activity. In attempting to make this relationship more understandable to his lay audience, he opened with the example of Penicillin G, a molecule commonly recognized as a powerful antibiotic.

Despite penicillin’s widespread application in medical contexts and its acknowledged significance to human life since its discovery in 1928, the molecule’s physiology, at the time of Pauling’s radio talk, was not well-understood. This circumstance was likewise true of other molecules that had become household names, including DDT, morphine, ether, and adrenaline. While scientists understood their uses and functions, the chemical activity that generates and determines those functions remained out of grasp.

Pauling believed that these connections, and the answers that they might provide, lay in what he called “their molecular architecture.” More specifically, were scientists able to determine the structures of specific molecules, they might then turn their attentions to the structures of the biochemical forms with which the molecule interacts. In the case of the household names molecules – penicillin, morphine and the like – these forms might include enzymes, nerve fibers, and tissues with which the molecules interact to produce a desired effect, such as killing bacteria or numbing pain.


Interatomic distance is one important aspect of molecular structure that Pauling took pains to emphasize to his audience. In order to convey a sense of the scale at which atomic distances are measured, Pauling created a hypothetical world where perspective was shifted in the direction of the commonplace. He began by stating that a single Angstrom – the unit used to measure interatomic distances – is equal to 1/254,000,000th of an inch. In other words, when magnified by a factor of 254 million, one scaled-up Angstrom unit would be equivalent to one inch.

With proportions thus shifted, the average human being in Pauling’s hypothetical world would be about 250,000 miles tall, and a wineglass would be as big as the Earth. Importantly, were this gargantuan wineglass full of liquid chloroform, each individual chloroform molecule would be a mere seven inches across. A molecule of chloroform is made up of one carbon atom, three chlorine atoms, and one hydrogen atom, and on this scale, the carbon atom would be the size of a walnut, each chlorine atom the size of a small orange, and the distance between the walnut and each orange would be 1.76 inches. Scaled back down to its actual size (that is, a wineglass-sized wineglass), that distance would be 1.76 Angstrom units.

Pauling’s point in developing this hypothetical was that, in part because they are both small and complicated, the structures of organic compounds were poorly understood. “This then is the great problem of modern chemistry,” Pauling suggested, “the determination of the molecular architecture of the proteins and other complex constituents of the living organism.”

Indeed, Pauling believed that progress in medicine was particularly dependent upon an improved understanding of molecular structure and physiology. By extension, he saw the future role of the “medical research man” as being equivalent to a “molecular architect.” Armed with an understanding of the molecular structures underlying physiological reactions, this new style of architect would have the ability to create “atomic blueprints” for pharmacological compounds designed specifically to treat particular illnesses.

Chairing the Division After the War: Progress Toward Pauling’s Post-War Plan

Linus Pauling, 1947

[Pauling as Administrator]

In January 1946, Linus Pauling presented his plan for a joint research program to be shared between the Division of Chemistry and Chemical Engineering and the Division of Biology at the California Institute of Technology. Delivered for the third time to the Institute’s Board of Trustees, Pauling’s vision called for

an expansion of the work of these Divisions during the next fifteen or twenty years, in order that a very promising field of investigation intermediate between chemistry and biology may be cultivated; this field of investigation is also very closely related to medicine.

In putting forth these ideas, Pauling sought to build and expand upon previous research successes that had emerged from support provided by the Rockefeller Foundation.

In his talk, Pauling noted that the past two decades had brought about the development of immunochemistry, chemical genetics, and the use of radioactive tracers. These breakthroughs had made more feasible the potential determination of the “structure and nature” of substances smaller than the cell­­ – enzymes, proteins, genes, and viruses – that are not visible under a microscope. But determining these structures, Pauling told the board, would require

a considerable expansion in chemistry and biology, with the addition to the staff of specialists in fields such as enzyme chemistry, nucleic acid chemistry, microbiology, general physiology, and virology.

In making his argument, Pauling brought Rockefeller administrator Warren Weaver into the mix by sharing “that in his opinion there is no place in the world so well suited for this work as the California Institute of Technology.” If the trustees agreed to go along, Pauling believed that the program could potentially bring in as much as $6 million worth of Rockefeller support to split between divisions and enable the construction of two new buildings.

While he had faith that the Rockefeller Foundation would provide significant external funding for his plan, Pauling also had his eye on other sources. One noteworthy resource in this regard was E. K. Wickman of the Commonwealth Fund, whom Pauling queried about granting capacity at the National Foundation for Infantile Paralysis. Wickman reviewed the foundation’s assets and earnings, and reported back that they likely had $10 million in their national reserves at the start of the year, and had since established a goal of raising another $25 million through their annual March of Dimes. Wickman added that this was a conservative estimate, and urged that

Considering that the National is now pricked by criticism for large accumulations, that it has just had fresh increases, and that as a relative newcomer in the philanthropic field it may want to establish a reputation in competition with the old foundations, you may well be coming to them at the right moment for a substantial grant.


Thus encouraged, Pauling, along with colleagues George Beadle and Alfred Sturtevant, drew up “A Proposed Program of Research on the Fundamental Problems of Biology and Medicine.” The proposal asked for $6 million over the next fifteen to twenty years and was submitted to the Rockefeller Foundation and the National Foundation for Infantile Paralysis. The overarching goal of the proposed program was to “uncover basic principles” in the biochemistry of medicine including the structure and mechanism of genes, a general understanding of viruses and antibodies, and the physiological basis of drugs. The authors also expected that plenty of practical discoveries would be made along the way.

The proposal placed special emphasis on the need to attract people trained in biology and medicine as graduate students and post-doctoral researchers. It pointed out that the number of graduate students working in the divisions authoring the proposal had dropped by more than twenty since the end of the war, a trend that would need to be stanched were the Institute to achieve new heights. Fortunately, at least in the authors’ views, Caltech was particularly well-positioned to support a new and ambitious program, one that would usher in “a period of great and fundamental progress, similar to that through which physics and chemistry have passed during the last thirty-five years.”


Once they had evaluated the proposal, the Rockefeller Foundation, as was their custom, asked for assurance that Caltech would continue to support biochemistry and biophysics with its own institutional resources. The foundation was also not prepared to support the construction of new buildings. (With this information in hand, Pauling and Beadle pressed Caltech President Lee DuBridge to earmark other Institute funds for constructing the new buildings.)

Ultimately the Rockefeller trustees agreed to provide a measure of support, but it fell far short of the proposal’s ambitious ask. A semiannual grant of $50,000 was allocated, to be paid out over seven years for a grand total of $700,000 in funding. The National Foundation for Infantile Paralysis also agreed to a partial measure: a five-year grant totaling $300,000.

Pauling, Beadle and Sturtevant were glad to have these pledges of support in hand and saw other routes to arriving at the $6 million original ask; among them a $2.3 million private bequest recently made to the Institute. With funding momentum gathering, Pauling decided that he would shorten his forthcoming Eastman residency at Oxford University so that he could devote more time to creating action items and managing budgets.


Once implemented, it did not take long for the new plan to show fruit. By 1947, Institute researchers had set upon an ambitious research agenda that included studies of the structure, composition and molecular weight of amino acids, peptides, proteins, and viruses; the chemistry of enzymes and nucleic acids; immunochemistry; serological genetics and embryology; chemical genetics; virology; and intermediary metabolism in plants and animals. Nascent and proposed research ideas also included electron microscopy studies of viruses and proteins; the chemistry of nucleic acids; and other topics in microbiology, physiology and biophysics.

And yet, despite the new money, adequate funding emerged as an uncertainty once news of a $240,000 budgeted shortfall began to circulate. As a corrective, the division started to look at other pots of money to cover the gap, including another large grant that had been promised by the Rockefeller Foundation, as well as smaller sources, like a $3,300 award that George Beadle had received from the Eli Lilly Company to work on the biosynthesis of vitamins. Certain funding lines however, including a five-year $75,000 grant that Pauling had secured in 1945 from Union Carbide to support fundamental research on the structure of metals and alloys, remained out of bounds.


The fresh funding coming in for biochemical work aligned nicely with President DuBridge’s emphasis on returning Caltech to its pre-war focus on fundamental research. A return of this sort was needed because the war years had pushed the Institute towards contract work that was funded by the government and private entities. These contracts were particularly attractive to faculty, as the deals often served as a source of extra income on top of their Caltech salaries.

Indeed, more money for individual use was becoming a necessity. Notably, a 1947 report commissioned by DuBridge showed that the cost of living in Pasadena had increased “well over 40 per cent” since the start of the decade. To keep pace with Harvard, Berkeley and MIT, Caltech would need to raise its salaries by 50% above 1940 levels, followed by an additional 75% increase over the next three years. At the time that the report was issued, Caltech had only boosted its salaries by 20% since the start of the war.

One solution that DuBridge found to address this problem that allowed him to also enforce Caltech’s existing restrictions on doing contract work, was to change the salary structure for faculty such that they were paid a twelve month salary at the same monthly rate as their nine month salary. In instituting this change, DuBridge effectively gave his faculty a raise that was equal to three months of pay.


In the meantime, Pauling continued to recruit new faculty into the Institute. He assisted E. C. Watson, Caltech’s Dean of Faculty, in looking for a mathematician and solid state physicist while he was in residency at Oxford. One name that Pauling put forth was Mary Cartwright of Cambridge, who had recently been named the first female fellow of the Royal Society and who came recommended as the “most outstanding younger mathematician in England.”

Pauling had less luck finding good physicists in England, but did recommend Clarence Zener of the University of Chicago’s Institute of Metals. The following month, Pauling suggested that Paul Dirac – then of the Institute for Advanced Study – be invited to Caltech, which Pauling felt he might consider for a professorship. Ultimately none of these suggestions worked out, but Pauling’s grander vision for post-war science at Caltech was unarguably moving forward.

Kevorkian, Pauling and a Twist on Capital Punishment

Page 1 of Kevorkian's 1958 paper on capital punishment and medical research.

The New York Times has published a detailed obituary of Dr. Jack Kevorkian, the medical pathologist famed for his active support and engagement with physician-assisted suicide.  Kevorkian died this morning in a Michigan hospital.  For us, news of his passing immediately brought to mind a fascinating exchange that he carried out with Linus Pauling in the 1970s.

As the Times piece briefly mentions, before he achieved international notoriety – and eventually imprisonment – for assisting the premature deaths of terminally ill individuals, Kevorkian lobbied in favor of a different death-related practice.  As first outlined in a 1958 paper, Kevorkian proposed that prisoners convicted to death be given the option of essentially donating their deaths to science.  The crux of Kevorkian’s proposal, which was delivered at a meeting of the American Association for the Advancement of Science, went as follows:

I propose that prisoners condemned to death under capital punishment be allowed to submit, by their own choice, to medical experimentation under surgical anesthesia, to be induced at the set minute of execution, as a form of execution in lieu of the conventional methods prescribed by law.

…Most of us are well aware that the ultimate ‘laboratory’ for testing every medical fact, concept or device is man himself….In this logical and proper sequence of trial, the human subject, at the end, the ‘guinea pig,’ is, and always will be, the most difficult link to procure.

…Viewing the problem purely realistically, capital punishment, as it exists today, offers an unrivaled opportunity to break these limits.  It can do this by introducing into the situation an involuntary factor without destroying the necessary safeguard of consent.

Kevorkian suggested that these types of medical experiments

should be funneled from all over the civilized world into a central agency, perhaps under the auspices of the United Nations….Of necessity, the experiments should be extremely imaginative, should deal with things completely uninvestigatable in living men under usual circumstances….Multiple experiments may be done simultaneously or sequentially on different parts or systems of a single body and could conceivably last for days under uninterrupted anesthesia stringently controlled by at least two board anesthesiologists.  If experimentation does not cause death, it would ultimately be induced by an overdose of the anesthetic agent.

Kevorkian points out that there would likely be “real and valid criticisms” to his proposal “from the legal side,” and that “for society, there would be some added financial expense.”  For the condemned, Kevorkian saw few disadvantages and “for medical research, there is no seeming disadvantage.”

Indeed, from the perspective of the prisoner, the prospect of dying for science could even mitigate a major philosophical objection to capital punishment.

In the case of the execution of innocent persons (a remote possibility), it would give the victim perhaps a little solace in having an opportunity to transform an ugly act of human injustice into one of some gain for mankind, at least, and to thereby partially rectify the otherwise total injustice of it all.

Kevorkian would extend his thoughts on this proposal in later articles and codify many of them in a 1960 book, Medical Research and the Death Penalty.  He also actively solicited the support of notable figures in favor of his idea.  In 1973 Kevorkian sent Pauling a packet of materials that included copies of letters that he had received from a number of scientists and physicians expressing their support – sometimes hedging – of the proposal.

Pauling appears to have lent an initial vote of support via a phone conversation that he and Kevorkian conducted in January 1973.  In a letter of thanks, Kevorkian writes

As emphasized in my papers, I neither support nor oppose capital punishment; my only contention is that wherever and whenever it is to be irrevocably used some condemned persons should be given this choice.  Even opponents to the death penalty (such as Dr. [Hans] Selye and yourself) have admitted that this proposal is a fair compromise and desirable if the death penalty is not to be totally abolished.

Later in the letter, Kevorkian requests a written statement of support from Pauling, for use in an upcoming hearing to be held by the Florida legislature.  Pauling responded in kind, writing “I support your proposal about an alternative method of capital punishment.”

Three and a half years later, in November 1976, Kevorkian wrote again, for the final time.  At that point, capital punishment in the U.S. had been suspended but, as Kevorkian noted, “it seems that we are on the verge of seeing a resumption of executions, perhaps soon in Utah.  I plan to resume my campaign and would like to know if you still endorse the idea and still allow me to cite your endorsement publicly.”

By now, Pauling was starting to have his doubts.  In a letter written promptly upon his receipt of Kevorkian’s request, he wrote

I am so busy at the present time that it would be difficult for me to look into the matter, and in fact my ideas have changed somewhat.  I think that the best form of execution, if people are to be executed, is the one that causes the person the least suffering.  I am not sure that this idea is compatible with your proposal.

No matter one’s ultimate opinion on Kevorkian’s proposal, the idea is unquestionably thought provoking.  For those interested in reading more on the subject, see the following:

  • “Capital Punishment or Capital Gain?” Original 1958 paper republished in Crime in America, Herbert A. Bloch, ed.  New York: Philosophical Library, 1961.
  • “Medical Research and the Death Penalty: A Dialogue,” J. Med. Ed., 35, 10, October 1960.  Later published in book form, New York: Vantage Press, 1960.  Second edition published by Poignant Press, 1983.
  • “The Nobler Execution,” Ararat, Summer 1961.

Vitamin C, the Common Cold and Controversy

By Tom Hager

[Part 3 of 3. For the full text of this article, originally presented as a lecture sponsored by Oregon Health Sciences University, please see this page, available at http://thomashager.net]

Portuguese edition of Vitamin C and the Common Cold, a book that was translated into nine different languages.

Pauling’s reading of the literature convinced him that the more vitamin C you took, approaching megadose levels, the lower your chances of getting sick, and the less sick you got.  It was at this point that Pauling made what I consider to be a fundamental mistake. He decided to publish his ideas without peer review, in the form of a popular book.

He did not feel he could wait. He had, he thought, good evidence that a cheap, apparently safe, easily available nutrient could prevent at least an appreciable fraction of a population from suffering through an affliction that made millions of people miserable. And there might be even greater results. Pauling had read of small villages, snowbound in the winter, where no one got colds because there was no reservoir of respiratory viruses to pass around. When visitors arrived in the spring, they would bring colds with them, and everyone would suffer. What if, through the use of vitamin C, a great many more people strengthened their resistance to colds? The two hundred or so cold viruses rampant in the world would have many fewer places to replicate themselves. The spread of colds would lessen; the population of cold viruses would decrease. “If the incidence of colds could be reduced enough throughout the world,” Pauling thought, “the common cold would dis­appear, as smallpox has in the British Isles. I foresee the achievement of this goal, perhaps within a decade or two, for some parts of the world.” Vitamin C, properly and widely used, might mean the end of the common cold.

Packaging for commercial cold remedies pasted by Pauling into his research notebook, July 1970.

This, of course, would not only greatly lessen the amount of suffer­ing in the world; it would increase the fame of Linus Pauling. He was nearing seventy years of age. It had been nearly twenty years since he had captured international attention for his scientific work with proteins, and won the Nobel Prize for chemistry. His efforts had gone to politics in the years since, and none of his recent scientific work had had much impact. Science was moving on without him. He was becoming a historical figure.

Pauling did not feel like one. He was not ready for emeritus status, trotted out at honorary occasions, shunted aside while the young men made the discoveries. He was still strong, still smart, still a fighter. Or­thomolecular medicine was the newest of his grand plans, and no one had shown that his ideas about creating an optimal molecular environ­ment for the body and mind were wrong. The evidence he had uncov­ered about ascorbic acid and colds, evidence that showed human health could be improved by increasing the amount of vitamin C in the body, was the strongest indication yet that he was right. Bringing it to the public’s attention would not only be good for the public; it would be a striking example of the correctness of his general theory.

Pauling’s book Vitamin C and the Common Cold, written in his usual clear, well-organized, straightforward style, presented the results of his literature search. He discussed the findings of five controlled trials that supported his idea, several anecdotal instances of physicians who had treated colds with vitamin C, and evidence that ascorbic acid was safe in large doses. Pauling felt confident that a several-gram daily dose would do no more harm than to cause loose stools, that vitamin C was safe, especially compared with potentially toxic, commonly avail­able over-the-counter medications such as aspirin. The rest of the book was a summary of his orthomolecular thinking and Irwin Stone’s ideas about evolution. A good deal of space was devoted to the topic of bio­chemical individuality, which resulted in a wide personal variation in the need for vitamin C and other nutrients.

On November 18, 1970, prepublication galleys were released to the press, and an unprecedented public roller-coaster ride began. The next day, the New York Times quoted Pauling as saying that humans needed between 1 and 4 grams of vitamin C per day to achieve optimal health and prevent colds. Pauling also took the occasion to slam the medical establishment – from drug companies to medical journals and physicians – for attempting to quash the evidence in favor of ascorbic acid. Why would they do that? the reporter asked. Look at the cold-remedy industry, Pauling said: It was worth $50 million per year, and that bought a lot of advertising space in medical magazines.

This quickly alienated both physicians and the editors of medical journals, neither of whom liked the implication that profits were more important than health. The medical establishment felt it necessary to respond, and respond quickly, once they saw how Pauling’s idea took off.

The book sold wildly, and so did vitamin C.  Pauling’s timing, at least on the public side, was superb. The 1960s had seen a resurgence of interest in “natural” health based on a holistic attitude that said body, mind, and soul were one. Many streams fed into this alternative health movement: a back-to-the-land, organic-foods orientation; a fas­cination with yoga, acupuncture, meditation, and other Eastern health practices; the rediscovery of the lost Western arts of naturopathy and homeopathy. Pauling’s message about vitamin C resonated with mil­lions of people who were reacting against corporate, reductionistic, paternalistic medicine, with its reliance on drug therapy, with people taking a renewed responsibility for their own health and trying to do it naturally. It was delivered just as natural food stores were popping up on corners in every town in America, each one stocked with a section for herbal remedies, a rack for magazines on alternative health regi­mens, and plenty of shelf space for vitamins.

The publication of Pauling’s book triggered a nationwide run on vitamin C. Sales skyrocketed, doubling, tripling, quadrupling, within a week of its appearance. Druggists interviewed in newspapers across the nation told of people coming in to buy all the vitamin C they had. Wholesale stocks were depleted. “The demand for ascorbic acid has now reached the point where it is taxing production capacity,” said a drug company spokesman less than a month after Pauling’s book ap­peared, adding, “It wouldn’t pay to increase production capacity since we’re sure it’s just a passing fad.”

The reaction was swift. The physician-head of the Food and Drug Administration (FDA), Charles C. Edwards, announced to the press that the national run on vitamin C was “ridiculous” and that “there is no scientific evidence and never have been any meaningful studies in­dicating that vitamin C is capable of preventing or curing colds.” The FDA, Pauling found, had proposed in 1966 that no vitamin C tablets over 100 mg be available without a prescription, and he responded to Edwards with sarcasm. If the FDA had its way and he wanted to take 10 grams of vitamin C to fight off a cold without going to a physician for a prescription, Pauling said, he would have to take 100 tablets. “I think I would have as much trouble swallowing all these tablets as I would swallowing some of the statements made by the Food and Drug Ad­ministration in proposing these regulations,” he said.

The medical press was equally critical of Pauling. The American Journal of Public Health said that Pauling’s book was “little more than theoretical speculation.” The Journal of the American Medical Association said of Pauling’s book, “Here are found, not the guarded statements of a philosopher or scientist seeking truths, but the clear, incisive sentences of an advertiser with something to sell. . . . The many admirers of Linus Pauling will wish he had not written this book.” The Medical Letter launched the harshest attack yet, saying Pauling’s conclusions “are derived from uncontrolled or inadequately controlled clinical studies, and from personal experience” and pointing out that there was no good evidence that vitamin C was safe when taken over a long period of time in large doses.

The controversy over Pauling’s book arose from a simple fact: He had not made his case. The book was a combination of his interesting but unproven speculations about orthomolecular medicine and the human evolutionary need for ascorbic acid, coupled with a select handful of studies that indicated that vitamin C could prevent or ame­liorate colds in a fraction of a population. That might make an inter­esting conference paper, but it was little reason to advocate a wholesale change in the dietary habits of a nation. His critics pointed out that he had no clear theory of how vitamin C exerted it powers and that there was no good study – no study at all – establishing that the long-term ingestion of megadoses of vitamin C was safe. The current dogma in the medical profession was that vitamins were needed only in the small amounts provided by a well-balanced diet. Taking grams of vitamin C every day might cause everything from gastric upset to kid­ney stones, and who knew what else?

The way he had gone about publicizing his ideas, sidestepping the normal channels of scientific peer review to publish a popular book, also fueled criticism. He was behaving like a health faddist, not a scien­tist. In the eyes of most physicians – generally conservative about new therapies, disdainful of the holistic health movement, trained to be­lieve that vitamin C was needed only to prevent scurvy – Pauling looked like a nutritional quack, a vitamin pusher who was essentially prescribing without a license.

Typically, Pauling fought back. To pursue his ideas, in 1973 he cofounded (with Arthur Robinson, a young colleague who later moved to Oregon and this year ran for Congress) the Institute of Orthomolecular Medicine in Palo Alto, California.

He went on to publish more books, adding the flu as another disease vitamin C could fight, then Vitamin C and Cancer, and finally compiled all his ideas into How to Live Longer and Feel Better.

Anecdote published in Chemtech, September 1994.

Criticism from the medical community has never let up. A general belief still exists in most – although not all – of the medical community that Pauling went off his rocker.

However, despite what many physicians believe, the jury is still out. A significant amount of active biomedical research research continues to examine the effects of micronutrients on a variety of conditions. For instance the Linus Pauling Institute at Oregon State University (successor to Pauling’s Orthomolecular Institute) maintains a highly successful research program in 12 laboratories funded with millions of dollars of competitive grant funding. The Institute’s head, Balz Frei, believes that Pauling’s basic approach remains sound – but that his arguments with physicians might have caused as much damage to the study of nutritional science as they did good. In my own view, by putting personal controversy ahead of reasoned consensus both Pauling and his critics polarized the public into groups that still have trouble communicating with each other.

Pauling’s work helped give birth to today’s booming market in nutritional supplements. Vitamin C remains the world’s largest-selling supplement. A large number of advocates strongly believe that ingesting vitamins in amounts far above the RDA can help optimize human health, especially by preventing chronic disease. There is a growing understanding that the key in these studies – as Pauling pointed out long ago – is not to look for vitamins to act like pharmaceuticals, exerting significant effects at low doses, but more like nutrients, with less dramatic effects that accumulate at much higher doses.

Linus Pauling himself lived an active life well into his nineties, performing useful research until the end. He was taking many grams of Vitamin C every day.

Will the controversy he started ever end? Was he a genius, or a crank?

The Birth of Orthomolecular Medicine

By Tom Hager

[Part 2 of 3.  For the full text of this article, originally presented as a lecture sponsored by Oregon Health Sciences University, please see this page, available at http://thomashager.net]

Linus Pauling and Irwin Stone, 1977.

The concept of orthomolecular medicine was Pauling’s grand theory of human health.

His approach was chemical, and viewed the body as a vast laboratory buzzing with chemical reactions: enzyme-substrate reactions, energy-producing reactions, antibody-antigen reactions, the chemical interactions that resulted in genetic duplication, and electrochemical reactions in the brain and nerves. Health, in this view, resulted when the lab was well-run and reactions were moving ahead properly; disease resulted if the proper reactions were hindered or stopped. Optimal health could be achieved by perfecting reaction conditions and making sure that the body maintained the proper balance of chemicals (nutrients, catalysts, and products).

After thinking about this balance for years, he coined a term to describe it: orthomolecular, meaning “the right molecules in the right amounts.”

He first used the term in print in 1967 in relation to psychiatric therapy. He had by then become convinced that conditions such as schizophrenia could be treated with nutrients such as niacin (an approach developed by Abram Hoffer and Humphrey Osmond). However, his theory of orthomolecular psychiatry was either ignored or criticized by the medical community.

Then came Vitamin C.


 

In March 1966, in a speech Pauling gave after receiving the Carl Neuberg Medal – awarded for his work in integrating new medical and biological knowledge – he men­tioned to the audience that he wanted to live another fifteen or twenty years in order to see the wonderful new medical advances that would surely come. A few days later, he received a letter from Irwin Stone, a gregarious Staten Island biochemist he had met briefly at the Neuberg dinner.

Stone told him how much he appreciated his talk and then wrote that asking for twenty more years of life was asking for too little. Why not live another fifty years? It was possible, if Pauling listened to his ad­vice.

Letter from Irwin Stone to Linus Pauling, April 4, 1966. This is the communication that spurred Pauling's interest in vitamin C.

He then told him about vitamin C.

Irwin Stone had been interested in vitamin C since 1935, when he began publishing papers and taking out patents on the use of ascorbic acid, or ascorbate (both synonyms for vitamin C), as a food preserva­tive. Over the years his interest grew as he read a series of scattered re­ports from around the world indicating that ascorbate in large doses might have some effect on treating a variety of viral diseases as well as heart disease and cancer. Convinced of its health-giving power, Stone and his wife started taking up to 3 grams of the vitamin per day- many times the daily dose recommended by the government.

Stone felt better as a result, but it took a car crash to make him a true believer. In 1960 Stone and his wife, driving in South Dakota, both nearly died when they were hit head-on by a drunk driver. They not only survived the crash, however, Stone told Pauling, but healed with miraculous rapidity. This he attributed to the massive doses of vitamin C they took while in recovery.

He emerged from the hospital ready to convince others about the value of ascorbate. He began to read widely, noting that among mam­mals, only man, closely related primates, and guinea pigs were unable to synthesize their own vitamin C internally because they lacked an en­zyme critical in producing the vitamin. As a result, humans had to ob­tain it through their diet. If there was none available, the result was scurvy, the dreaded ailment that had killed thousands of sailors before a British physician discovered it could be prevented by providing lime juice or fresh oranges. The U.S. government had duly set the mini­mum daily requirement for vitamin C at a level just sufficient to pre­vent scurvy.

But Stone believed that it was not enough. Scurvy was not a simple nutritional deficiency, it was a genetic disease, the lethal end point of an inborn error of metabolism, the loss of an enzyme that robbed hu­mans of the ability to produce a needed substance. And it appeared from animal studies that simply preventing scurvy might not be enough to ensure optimal health. Only one good biochemical assess­ment of ascorbic acid production in another mammal had been done, on rats, and it indicated that on a weight-adjusted basis, a 150-pound adult human would need between 1.4 and 4 grams of vitamin C per day to match what rats produced to keep themselves healthy. Stone was convinced that taking less than this amount could cause what he called “chronic subclinical scurvy,” a weakened state in which people were more susceptible to a variety of diseases. In a paper he had writ­ten- and which had already been rejected by six medical journals – he concluded,

This genetic-disease concept provides the necessary rationale for the use of large doses of ascorbic acid in diseases other than scurvy and opens wide areas of clinical research, previously inadequately explored, for the therapeutic use of high levels of ascorbic acid in infectious diseases, collagen diseases, cardiovascular conditions, cancer and the aging process.

In other words, to Stone, giving someone enough vitamin C to pre­vent scurvy was like feeding them just enough to keep them from starv­ing. Full, robust health demanded more. He advised that Pauling start with about one and a half grams per day. It was especially good, Stone said, for preventing viral diseases like colds.

“I didn’t believe it,” Pauling later said jokingly of Stone’s letter. After all, Stone was no physician, nor was he a nutritionist exactly or a professional medical researcher.

Pauling's response to Stone's letter of April 4, 1966. Written in July 1966.

But Pauling was interested enough to try taking more vitamin C himself. He discovered that it helped him fight off the colds that had frequently afflicted him. He felt better. He took a little more. Then more.

But he told few people about it. He remained generally silent about ascorbic acid and its benefits through the late 1960s, limiting his few comments to ideas about how it might be used, along with other nutrients, in the treatment of schizo­phrenics. In late 1969, however, convinced by the theoretical argu­ments of Irwin Stone and impressed by his own success in preventing colds, Pauling began expanding his comments to include the subject of ascorbate and general health, noting in a speech he gave to physi­cians at the Mt. Sinai Medical School his success with the use of vita­min C as a cold preventive. His comments were reported in the newspapers.


Cartoon of Linus Pauling in the laboratory, by Sidney Harris. 1985.

That is how it began. Then, two things happened. First, he received a “very strongly worded” letter from Dr. Victor Herbert, a leading clinical nutritionist and a man who helped set the U.S. recommended daily allowances (RDAs) for vita­mins, who assailed Pauling for giving aid and comfort to the quacks who were bleeding the American public with unsupported claims about the benefits of vitamins. Where, Herbert asked, were the care­fully controlled clinical studies to prove that ascorbic acid had a real effect on colds?

Pauling was taken aback. He had not, in fact, carefully reviewed the literature on vitamin C, limiting his reading to a few of the cita­tions in Irwin Stone’s original papers. But now, “sufficiently irritated by this fellow Herbert,” he began a typically comprehensive tour of the scientific journals.

Second, a writer for Mademoiselle magazine contacted Pauling to get his comments on vitamin C for an article on its health benefits. Pauling offered the reporter the general observation that “optimal amounts of vitamin C will increase health and intelligence” and re­ferred readers to his paper on orthomolecular psychiatry. When the article appeared in November 1969, he found his statement rebutted by Frederick Stare, a professor of nutrition at Harvard, who said Paul­ing “is not an authority on nutrition” and that there was no evidence that increased C helped prevent the common cold; in fact, just the op­posite was true. A large-scale study done with five thousand students in Minnesota twenty years earlier, Stare said, had proven definitively that vitamin C had no effect on colds.

Stung, Pauling quickly tracked down the study and decided that Stare had gotten his facts wrong. The 1942 University of Minnesota study involved 363 student subjects who had been given either a placebo or some extra ascorbic acid over a period of twenty-eight weeks. It was true that the authors had concluded in their summary that there was no “important effect” of vitamin C on infec­tions of the upper respiratory tract. But when Pauling took a closer look at their data, he decided they were wrong. Despite what Pauling considered the very low dose of vitamin C given the students – an aver­age of 180 mg per day compared to the 3,000 mg Pauling was now tak­ing – the researchers had in fact seen an effect:  Subjects receiving the extra vitamin had 15 percent fewer colds, and the colds they got were 30 percent less severe than those receiving the placebo. Vitamin C was not a preventive or cure, but the results were, Pauling estimated, statis­tically significant.

It was confusing, especially when Pauling saw the same thing hap­pening in other reports he found on vitamin C and colds: Partial ef­fects were discounted. The physicians who ran the studies seemed to be looking for total cures, not an indication of an effect. The doses they used were low (150-250 mg was common in these early studies –  several times the current RDA but many times lower than what Pauling and Stone considered a protective dose), and the effects they looked for were too strong.

The problem, Pauling decided, was that the researchers were look­ing for vitamin C to act like a drug. In traditional drug testing, small differences in dosage could have tremendous effects, and overdoses were deadly. The tendency was to use relatively small amounts and look for big effects.

Pauling research notebook entry on Gunther Ritzel's 1961 study. Notes dated February 22, 1971.

But to Pauling, vitamin C was a nutrient, not a drug. When the medical researchers saw a small effect, he thought the logical next step should have been to follow up with larger doses. His literature search uncovered at least one study that showed what might happen if they did. In 1961 a Swiss researcher named Gunther Ritzel had given half of a group of 279 skiers 1,000 mg per day of vitamin C – more than five times the Minnesota dose – and the other half a placebo. Ritzel found that those skiers receiving ascorbic acid had 61 percent fewer days of illness from upper respiratory tract infections and a 65 percent decrease in the severity of their symptoms compared to the placebo group.

This, Pauling thought, was very strong evidence in favor of his ideas. Plot the dose of vitamin C along the bottom of a graph and the effects on colds up the side and you could draw a straight line from the Minnesota results (a small effect with small dose) to the Swiss findings (a larger effect with larger dose). He found a few other papers in which the results fit the pattern. True, some of the research he looked at showed no effect at all – most of these studies, Pauling estimated, were flawed because they used too low doses, too short duration, shoddy oversight, or improper blinding – but the important thing was that a small group of careful clinical studies existed that supported Pauling and Stone’s general theory of vitamin C and health: The more C you took, approaching megadose levels, the lower your chances of getting sick, and the less sick you got.

The Medical Research of Linus Pauling

By Tom Hager

[Ed Note:  In October 2010, Pauling biographer Tom Hager delivered a talk sponsored by the Oregon Health Sciences University which detailed and discussed the various contributions that Linus Pauling made to the medical sciences, including the controversy over his strong interest in orthomolecular medicine.   With the author’s permission, excerpts of this talk are being presented on the Pauling Blog over the next three posts.  The full text of Hager’s OHSU lecture is available here.  Those with an interest in learning more about Hager’s work, including his latest research on food issues and world hunger, are encouraged to visit his blog at http://thomashager.net.]

[Part 1 of 3]

Oil portrait of Linus Pauling, featuring a model of the alpha-helix in the foreground. 1951. Portrait by Leon Tadrick.

By 1939, at the age of 38, Linus Pauling was a full professor and head of the chemistry division at Caltech, as well as the father of four children (three sons, Linus, Jr., Peter, and Crellin; and a daughter, Linda).

He was also beginning to turn his considerable talents toward understanding the complicated molecules inside the human body. He started with proteins.

The Molecules of Life

Determining the structure of proteins at this time was a gigantic problem. Most were difficult to purify, easily degraded, and hard to characterize. Proteins appeared to be not only gigantic, comprising hundreds or thousands of atoms – much too large to solve directly with x-ray crystallography – but also relatively fragile, losing their function (denaturing) after even slight heating or mechanical disturbance. No one at the time was even sure that they were distinct molecules – one popular theory held that proteins formed amorphous colloids, gels that did not lend themselves to molecular study.

Studying them at the molecular level seemed an impossible task with the tools available in the late 1930s. But Pauling took on the challenge. He started with the building blocks of proteins, the amino acids, and directed his growing lab team toward pinning down their precise structures. Then he set himself to figuring out how they formed protein molecules, often building models out of wood, wire, and paper.

He based his approach in part on the ideas of the German biochemist Emil Fischer. Like Fischer, Pauling came to believe that proteins were long molecular chains of amino acids linked end-to-end. Working with Alfred Mirsky in the mid-1930s, Pauling discovered that the denaturing of proteins resulted from breaking weak bonds, called hydrogen bonds, that pinned these chains into specific shapes. Between the early 1930s and early 1950s he made a string of important discoveries about hemoglobin, antibodies (including the most sophisticated work at the time into the structural relationship between antibody and antigen), enzymes, and other proteins.

Foldable paper model of the alpha-helix protein structure published in the Japanese journal Chemical Field, 1954.

In May 1951, he put everything he knew into a celebrated series of seven papers detailing the structures of a number of proteins at the level of individual atoms, including the structure of the single most important basic form of protein, the alpha helix (a hydrogen-bonded helical chain that is a structural component of almost every protein). It was an astounding breakthrough, and it opened the door for an understanding of biology at the molecular level. Within two years, Watson and Crick had used his approach to decipher the structure of DNA.

Biological Specificity

But structure was not everything. Pauling realized that life resulted not from individual molecules, but from the interactions between them. How did organisms make offspring that carried their specific characteristics? How did enzymes recognize and bind precisely to specific substrate molecules? How did antibodies recognize and bind to specific antigens? How did proteins, these flexible, delicate, complex molecules, have the exquisite ability to recognize and interact with target molecules?

It all fell under the heading of biological specificity at the molecular level. Pauling directed much of his attention here during through the 1940s, performing a great deal of careful work on the binding of antigens to antibodies.

Drawings of antibodies and antigens made by Linus Pauling in the 1940s.

His findings were surprising. Pauling demonstrated that the precise binding of antigen to antibody was accomplished not by typical chemical means – that is, through covalent or ionic bonds — but solely through shape. Antibodies recognized and bound to antigens because one fit the other, as a glove fits a hand. Their shapes were complementary. When the fit was tight, the surfaces of antibody and antigen came into very close contact, making possible the formation of many weak links that operated at close quarters and were considered relatively unimportant in traditional chemistry — van der Waals’ forces, hydrogen bonds, and so forth. To work, the fit had to be incredibly precise. Even a single atom out of place could significantly affect the binding.

Having demonstrated the importance of complementary structure with antibodies, Pauling extended his idea to other biological systems, including the interaction of enzymes with substrates, odors with olfactory receptors, and to the possibility of complementary structure in genes.

Pauling’s idea that biological specificity was due in great part to complementary “fitting” of large molecules to one another proved to be essential in the development of molecular biology. His research now formed a coherent arc, from his early work on the chemical bond as a determinant of molecular structure, through the structures of large molecules (first inorganic substances, then biomolecules), to the interactions between large biomolecules.

He carried out much of this research during World War II, when he also worked on synthetic plasma substitutes and a fruitless search for ways to produce artificial antibodies.

He had already earned a place among the nation’s leading researchers in the medical applications of chemistry. But his greatest triumph was still to come.

Sickle-Cell Anemia

Toward the end of World War II, Pauling’s reputation was great enough to earn him an invitation to join a national committee that was brainstorming the best structures for postwar medical research. This committee’s work led to the foundation of the National Institutes of Health.

Pauling was the only non-physician asked to join the committee.

At a dinner with other members one night, talk turned to a rare blood disorder called sickle-cell anemia. One of his dinner companions described how red blood cells in the victims were twisted into sickle shapes instead of discs. The distortion appeared to hinder the blood cells’ transport through capillaries, resulting in joint pain, blood clots, and death. The disease primarily affected Africans and African Americans. What caught Pauling’s attention most, however, was one odd fact: Sickled cells appeared most often in venous blood, rather than in the more oxygenated blood found in the arteries.

Pastel drawing of sickled Hemoglobin cells, 1964. Drawing by Roger Hayward.

He thought about this during the next few days. From his previous work with blood, he knew that red cells were little more than bags stuffed with hemoglobin. He had also shown that hemoglobin changed its shape slightly when it was oxygenated. If the red cells were changing shape, perhaps it was because the hemoglobin was altered in some way. What if the hemoglobin molecules in sickle-cell patients were changed in some way that made them clump, stick to one another, as antigens stick to antibodies? Perhaps something had changed that made the hemoglobin molecules complementary in shape. Perhaps adding oxygen reduced the stickiness by changing the molecules’ shape.

He presented his ideas as a research problem to Harvey Itano, a young physician who was then working on his Ph.D. in Pauling’s laboratory. Itano, later joined by postdoctoral fellow John Singer, worked for a year trying to see if sickle-cell hemoglobin was shaped differently from normal hemoglobin. They found no detectable differences in any of the tests they devised. But they kept at it. Finally, in 1949, using an exquisitely sensitive new technique called electrophoresis that separated molecules by their electric charge, they found their answer: Sickle-cell hemoglobin carried more positive charges on its surface.

This was an astounding discovery. A slight change in the electrical charge of a single type of molecule in the body could spell the difference between life and death. Never before had the cause of a disease been traced to a molecule. This discovery – to which Pauling attached the memorable title “molecular disease” – received widespread attention. Itano and Singer’s followup work demonstrated the pattern of inheritance for the disease, firmly wedding molecular medicine to genetics.

Medical Chemistry

It was a great triumph – there was talk of a Nobel Prize in Medicine or Physiology for Pauling – and it led Pauling to make greater efforts in the medical field. He encouraged M.D./Ph.D. candidates, hired physicians to work in his laboratory, and began focusing his own research on medical problems, including developing a new theory of anesthesia.

He was ahead of his time. An example of what the atmosphere was like: Pauling noted that as he went around in the late 1940s seeking funds for a comprehensive marriage of biology and chemistry to attack medical problems, people at funding agencies were telling him that they found the term “medical chemistry” to be “a disturbing description.”

In the late 1950s, Pauling extended his concept of molecular disease to the brain. After reading about phenylketonuria (PKU) – a condition in which a mental defect can be caused by the body’s inability to metabolize an amino acid, phenylalanine, leading to a buildup of that substance and others in the blood and urine – Pauling theorized that the problem might be caused by a defect in an enzyme needed to break down phenylalanine. PKU, in other words, might be another molecular disease. Now interested in the possibility that there might exist a range of molecular mental defects, Pauling visited a local mental hospital, saw other patients whose diseases seemed hereditary, and decided to seek support for an investigation into the molecular basis of mental disease. The Ford Foundation in 1956 awarded him $450,000 for five years’ work – a vindication of Pauling’s approach and a tribute to his reputation. The grant, however, yielded little in the way of immediate results, with much of the funding going toward testing his (ultimately found to be mistaken) theory of anesthesia.

The long-term results were more significant. Pauling’s immersion in the field, thanks to the Ford grant, led him to read widely in psychiatry and general health, always on the lookout for another molecular disease that might lend itself to new therapy. By the mid-1960s he was coalescing his findings into another overarching theory, this one combining much of what he knew about chemistry and health. He called his new idea “orthomolecular” medicine.