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.
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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.