Department of Chemistry, King's College London, London, UK WC2R 2LS
5 Molecular Medicine
After resigning from Caltech, Pauling accepted a position 1964-1967 at the Santa Barbara Center for the Study of Democratic Institutions. The Center had no laboratories, being devoted to the social sciences, and Pauling turned to theoretical studies of atomic nuclei and to evolutionary and medical issues arising from his earlier work in biological chemistry. He developed a close-pack spheron theory of nuclear properties, but physicists were unimpressed and he soon abandoned this field. Since his interests in biological and medical chemistry required access to laboratory facilities, he moved on to the University of California at San Diego 1967-1969, and then the University of Stanford 1969-1971. A network of supporters organised the funding and maintenance 1974-1994 of his own centre, the Linus Pauling Institute of Science and Medicine, at Palo Alto, California.
Pauling’s concerns with medical chemistry dated back to his early studies of haemoglobins. He had close contacts with the biologists at Caltech, particularly the geneticists studying the mutations produced by X-rays in the fruitfly, then in a simpler organism, the pink bread mould Neurospora crassa. George Beadle (1903-1989) and Edward Tatum (1909-1975) traced out the biosynthetic pathways in Neurospora by generating mutants which could no longer produce an intermediate substance in a given metabolic sequence, and so required the addition of that substance for normal growth. Their studies from 1941 created the new field of biochemical genetics, with the slogan ‘one gene-one enzyme’.
The work, recognised by the award of the 1958 Nobel Prize for medicine or physiology to Beadle, Tatum and Joshua Lederberg, drew attention to the long-neglected medical studies of Archibald Garrod (1857-1936) at St. Bartholomew’s Hospital, London. Garrod investigated rare inherited diseases running in families, such as the production of black urine (alcaptonuria) and analogous disorders. Garrod in his book, Inborn Error of Metabolism (1909, 1923) ascribed such diseases to a genetic error of recessive Mendelian character, leading to the loss or malfunction of an enzyme essential for a particular step in normal metabolism.
Pauling drew on the new field of biochemical genetics for his characterisation of inherited haemoglobin abnormalities as molecular diseases. He developed the view that the human nutritional needs for the vitamins, due to the genetic loss of stages in common metabolic pathways, were not always met by normal foodstuffs, and often required augmentation. The loss of a capacity to manufacture essential biomolecules, available from foodstuffs, had lightened the overall biosynthetic load, giving the affected organisms an advantage in natural selection. Thus, organisms had developed the biosynthesis of ascorbic acid, vitamin C, as an anti-oxidant when photosynthetic oxygen began to appear in the atmosphere. Some 25 million years ago the common ancestor of the hominids and other primate species lost the liver enzyme converting L-gulonolactone to ascorbic acid, following a genetic mutation. Other mammalian species, except for the guinea pig and a fruit-eating bat, retained vitamin C biosynthesis, as did most of the vertebrate species.
The loss of vitamin C biosynthesis had little adverse affect on the early development of humankind, judging from the skeletons of palaeolithic hunter-gatherers, who appear to have been as large and well-built as modern Americans. Following the development of agriculture, and the early urban civilisations, the human diet was based largely on grains, which produced small and stunted people, judging again by their skeletal remains. From the l6th century on, the long voyages of geographical exploration, and then of overseas trade and colonisation, promoted the deficiency disease of scurvy, alleviated by the addition of citrus fruit juice to the diet. Early 20th century studies of such deficiency diseases resulted in the discovery of the vitamins and their biochemical role in normal human metabolism.
Pauling noted that many people in modern urban societies live close to the edge of vitamin deficiency. The National Research Council under the US National Academy of Sciences has a Committee on the Feeding of Laboratory Animals, and a Food and Nutrition Board concerned with human diet. The Committee recommends an optimum daily intake of vitamin C (ascorbic acid) for laboratory primates, between 1.75 grams per day for rhesus monkeys and 3.50 grams per day for squirrel monkeys, scaled to 70 kg body mass. The Nutrition Board, however, recommends a human allowance of only 60 milligrams per day, corresponding to the minimum human intake of vitamin C required to avoid scurvy. Animals which manufacture their own ascorbic acid produce an average of ca. 10 g per day, scaled to 70 kg body mass. Pauling deduced that the diet of an adult human should contain at least 2.3 to l0 g of vitamin C per day.
The human immune system depends for efficient action on the vitamin level available in its several components, and some of these levels are depleted during a viral attack. The common cold virus reduces by one half the vitamin C level in leucocytes, impairing their action as phagocyctes. A regular daily intake of 0.25 to 4 g of the vitamin decreases the chances of catching a cold or influenza and of developing a secondary bacterial infection. Some 16 trails, with placebo-taking controls, showed a decrease in illness of 34% on average, even though the daily dose of vitamin C administered, 0.07 to ca. 1 g, was smaller than the dose Pauling recommended, Pauling found that the habitual colds from which he suffered were reduced in number and severity by taking several grams of vitamin C each day from the mid-1960s, as described in his book, Vitamin C and the Common Cold (1970), which enjoyed wide popular appeal. By the 1990s substantial support had emerged for a reduction of the severity, if not the frequency, of common colds by vitamin C administration.
The medical profession in general dismissed Pauling’s work, but individual physicians had made similar or related trials and reported their experience to him. In 1971, Pauling heard from Ewan Cameron, surgeon of the Vale of Levan Hospital near Glasgow, who had treated terminal cancer patients with l0 g of vitamin C a day over several years, finding that the treatment extended the survival time and the quality of life of his patients. Cameron held that vitamin C reinforced connective tissues that were weakened in cancer as in scurvy. Collaboration followed, with trials of vitamin C for the treatment of animal cancer at Pauling’s Institute, and the visit of Cameron for a year in 1978, resulting in a joint publication of the book, Cancer and Vitamin C (1979). The US National Cancer Institute (NCI) sponsored trials in the 1970s which reported no benefit to cancer patients from large doses of vitamin C. Pauling pointed out that Cameron’s protocol had not been adopted in these trials. By 1990, the NCI was more sympathetic, and sponsored an international symposium on ‘Vitamin C and Cancer’ with Pauling as a main speaker. The symposium, and a New York Academy of Sciences meeting in 1992, brought to light the general role of vitamin C and vitamin E as antioxidants, quenching the free radicals implicated in the genesis of cancer and other maladies.38
In his last book, How to Live Longer and Feel Better (1986), Pauling summarised the evidence and outlined the potential of his ‘orthomolecular medicine’. His therapy involved the boosting of normal essential metabolites to an optimum level, usually higher during illness than in normal health. These substances are generally limited in supply from foodstuffs or commensal gut flora, and have a wide range of beneficial functions and of tolerance in the body. In contrast conventional medicine involved the administration of physiologically alien natural or synthetic pharmaceutical products, with specific therapeutic effects, undesirable side-effects, and often-limited tolerance. His approach led Pauling to support and popularise medical reports of the value of vitamin treatments of viral and cardiovascular diseases, cancer, some forms of mental retardation or mental disorder, allergies, arthritis and rheumatism, and the moderation of the infirmities of old age.
Pauling attracted the support of physicians in the Orthomolecular Medical Association, which numbered some 500 members by 1986. Albert Szent-Györgyi (1893-1986) who had first isolated ascorbic acid in 1928, receiving the 1937 Nobel Prize in medicine and physiology for his discovery of the biochemical dicarboxylic-acid oxidation cycle, joined the crusade for vitamin C supplementation, as did other biochemists. Szent-Györgyi wrote in 1970 that the medical profession misled the public by specifying only the ascorbic acid intake required to avoid scurvy, which he called ‘a premortal syndrome’. The optimum vitamin C intake was uncertain, but Szent-Györgyi considered it to be much higher than the medical recommendation, and he himself took about a gram a day. Pauling allowed for biochemical individuality, recommending his readers to discover their own optimum daily intake of vitamin C, which he thought probably lay between 6 and 18 g. He specified a daily supplementation of other vitamins and minerals, together with regular exercise and dietary moderation, particularly sucrose and alcohol, to promote a general regimen for longer life and better health.