MYTH 22

THAT LINUS PAULING’S DISCOVERY OF THE MOLECULAR BASIS OF SICKLE-CELL ANEMIA REVOLUTIONIZED MEDICAL PRACTICE

Bruno J. Strasser

It has taken us almost half a century to cross the threshold from laboratory to clinic with respect to this genetic anemia, the “first molecular disease.”

—A. N. Schechter and G. P. Rogers, “Sickle Cell Anemia: Basic Research Reaches the Clinic” (1995)

How Are Human Disorders Caused by Single Genes Inherited?… Sickle-cell anemia, a recessive disease in which defective hemoglobin is produced, results from a specific mutation in the hemoglobin gene.

—Teresa Audesirk, Gerald Audesirk, and Bruce E. Byers, Biology: Life on Earth (2011)

There is a gene for breast cancer and one for Alzheimer disease and yet another one for obesity and one for alcoholism. The view that single genes uniquely determine complex human traits and that the solution to these diseases lies in the study of these genes is so prevalent today that it can easily go unnoticed. It is rooted, at least in part, in a powerful myth in the history of science: that Linus Pauling’s (1901–1994) discovery of the molecular basis of sickle-cell disease led to therapeutic improvement for patients.¹

In 1949, Pauling, perhaps the greatest physical chemist of his day, who eventually won two Nobel Prizes, published a paper in Science entitled “Sickle Cell Anemia, a Molecular Disease.” There he showed that the hemoglobin molecules of patients who suffered from the disease, causing severe pain and other symptoms, differed from the hemoglobin molecules of those who did not. More precisely, sickle-cell anemia hemoglobin exhibited a different electric charge, as seen in an electrophoresis apparatus, than did normal hemoglobin. Because the disease was known to be inherited in a Mendelian way, Pauling’s result has been taken to mean that a single gene, and the resulting molecule, could determine the occurrence of a disease. Since then, Pauling’s paper has been cited almost two thousand times in the scientific literature. More important, it has been included in almost all high school and undergraduate biology textbooks to explain “how human disorders [are] caused by single genes inherited,” as one typical textbook put it. For more than half a century, generations of students have learned about the relationship between genes and diseases through this example. After Mendel’s peas, Pauling’s sickle-cell anemia hemoglobin has been the inescapable story to show how genes (and molecules) determine complex traits.2

But Pauling’s breakthrough is also used to illustrate a broader point. It is presented as a model of how medical research should be conducted. Beginning in the laboratory, medical research will reveal the true cause of disease, leading to the discovery of new therapeutics to treat patients in the clinic. This model lies at the heart of contemporary biomedicine as a research practice. Since Pauling’s work, other examples of medical successes have been used to make the same two points (for example, the genetic disorders PKU and cystic fibrosis), but none has gained the popularity of sickle-cell anemia, which has become a powerful myth and an emblem for a specific research agenda.

Myths, as the French linguist Roland Barthes (1915–1980) put it in his Mythologies, are not simply inaccurate statements about the world; they are a specific kind of speech. Myths are a way of collectively expressing something about values, beliefs, and aspirations, even though, taken literally, the content of the myth is not true. As part of the collective memory of every community, myths have an effect on people’s identities and destiny. In science, the collective memory of the past shapes research agendas (what questions are worth pursuing) and disciplinary boundaries (who belongs to one discipline or another). Thus, myths not only (imperfectly) reflect the past but also shape the future. For this reason, explaining how and why a myth crystallized in a particular community at a specific time in history is often more illuminating than simply debunking the myth by showing its inaccuracies.3

Pauling’s Myth about “Molecular Medicine”

The myth constructed around Pauling’s discovery focuses on how his molecular approach to the disease “introduced the era of molecular medicine,” opening up a successful “rational approach to chemotherapy” and leading to “therapeutic progress” for patients. None of these points is historically accurate, and showing why they are not is revealing about both the history of the life sciences and the history of medicine in the twentieth century.⁴

The precise meaning of “molecular medicine” is rather unclear. But investigations about the relationship between (macro)molecules and diseases were common in the decades before Pauling’s paper. The biochemist Frederick Gowland Hopkins’s (1861–1947) work on vitamins, for example, established the importance of vitamins in health and disease. A year before Pauling’s publication, a hundred-page review described dozens of diseases that had been correlated with quantitative and qualitative alterations of blood proteins examined by electrophoresis, the same technique used by Pauling and his collaborators. Pauling was original in that he was the first to provide “a direct link between the existence of a ‘defective’ hemoglobin molecule and the pathological consequences of sickle cell disease.” For Pauling, the mechanism was rather simple: “the sickle cell anemia hemoglobin molecules might be capable of interacting with one another … to cause at least a partial alignment of the molecules within the cell, resulting … in the cell’s membrane being distorted” and the red blood cells adopting their characteristic sickled shape and the resulting impairment of blood circulation. Thus, Pauling did not introduce “the era of molecular medicine,” though he did indeed provide a convincing example of how the etiology (or cause) of a disease could be explained in molecular terms.5

Medicine is not only concerned with identifying the causes of diseases; it also aims to treat or, ideally, cure diseases. Behind the claim that Pauling introduced a “rational approach to chemotherapy” lies the criticism that earlier approaches to chemotherapy, such as screening, were “irrational” and unsuccessful. Neither is true. The German physician Paul Ehrlich’s (1854–1915) quest for a treatment against syphilis, leading to the first successful chemotherapy, was indeed the result of weeks of tedious testing of chemical compounds until the 606th finally yielded therapeutic benefits. But the choice of the compounds was not irrational. It rested on Ehrlich’s theory that if chemical dyes could color cells, it was because they bound chemically to organic matter and thus would constitute good candidates for having a biological effect. The greatest drugs of the twentieth century, from the sulfa drugs to antibiotics to cancer medications, were in large part the result of a similar approach.⁶

The myth is correct in describing Pauling’s vision: a detailed molecular understanding of the mechanisms of disease should directly lead to the identification of therapeutic molecules. Immediately after postulating that the interaction between abnormal hemoglobin molecules caused deformation of the red blood cells, Pauling suggested that the chemical that prevented this interaction could cure the disease. It is rarely known that Pauling worked for several years with a physician to test the effect of several molecules on the sickling process. The clinical results all proved negative. The tested molecules did indeed prevent the interaction with hemoglobin, but they also had many other, often toxic, effects. Although Pauling endorsed the view that “man is simply a collection of molecules,” the treatment of “man” turned out to be far more complex than he initially envisioned.⁷

Better known is the fact that Pauling considered another way to eliminate sickle-cell disease: eugenics. In 1968, he went so far as to suggest that “there should be tattooed on the forehead of every young person a symbol showing possession of the sickle-cell gene.” A few years earlier, he had argued that the chance that two parents carrying a mutation causing the sickle-cell disease would transmit it to their child was far too high (25 percent) “to let private enterprise in love combined with ignorance take care of the matter.” Except for some limited cases in which mandatory policies have been put in place to control for genetic diseases in populations (such as in Cyprus and Sardinia, where thalassemias are common), the focus of therapeutic measure has been on individuals and their “defective” molecules, following Pauling’s initially unsuccessful vision.8

One could claim that Pauling was only a bit ahead of his time and that his views eventually became vindicated. As two researchers at the National Institutes of Health put it in 1995, “it has taken us almost half a century to cross the threshold from laboratory to clinic with respect to … the ‘first molecular disease.’ ” At last, the authors claimed in the title of their paper, “Basic Research Reaches the Clinic.” But the clinical reality of sickle-cell anemia is far more nuanced, even today—twenty years later—than that comment suggests. Indeed, the understanding of the molecular mechanisms of sickling has led to many insights about potential therapeutic agents, but to this day none has reached the clinic. It takes more to transform the clinical reality of patients than a promising in vitro experiment or an animal trial. The only chemotherapeutic agent for sickle-cell anemia that has been brought to the market, hydroxyurea, increases the production of fetal hemoglobin among adults, thus preventing the interaction among abnormal hemoglobin molecules, as Pauling envisioned. Far from constituting a cure, it is part of the management of pain episodes for sickle-cell patients (a standard treatment unrelated to Pauling’s insight). Furthermore, the development of hydroxyurea was not the result of a “rational approach to chemotherapy” based on laboratory research, but of unexpected clinical observations by a pediatrician and epidemiological observations of adult populations who produce fetal hemoglobin.9

Occasionally, knowledge of the molecular basis of sickle-cell disease has contributed to improvement in therapy. Indeed, newborn screening for sickle-cell anemia is mandated in the United States and elsewhere and is conducted through the identification of abnormal hemoglobin that allows the early diagnosis of sickle-cell disease with great certainty and the beginning of prophylactic treatment for some of the consequences of the disease. But in most parts of the world, diagnosis is carried out through the much simpler and cheaper method of observing sickled blood cells under the microscope, following the method developed by the clinician James B. Herrick (1861–1954) in 1910.¹⁰

The myth that the discovery of the molecular basis of sickle-cell anemia led to improvements in therapy did not arise by accident. Immediately after the publication of his landmark paper, Pauling went on a crusade to popularize his vision of medical research. In general magazines and scientific journals, as well as at conferences given in the United States, Europe, and Asia, he repeated over and again how the search for molecular abnormalities would eventually lead to cures. In 1952, one newspaper typically carried the title: “Scientist Heralds New Era in Medicine Based on Studies of Molecular Action.” Pauling emphasized the broad relevance of his work, claiming that “most cases of mental deficiency can be attributed to molecular diseases.” He felt “confident that this knowledge will permit the deduction of improved therapeutic methods.” At several conferences, he argued that medicine would be “transformed from its present empirical form into the science of molecular medicine.” Pauling also attempted (unsuccessfully) to establish a medical research institute at the California Institute of Technology and carried out extensive research (with few results) on the molecular basis of mental diseases. His medical research resonated with his political activism against nuclear fallout, which caused many “molecular diseases.”11

Pauling’s vision about the relationship between laboratory research and clinical applications was embraced by many molecular biologists who were attempting to establish their new discipline in academic institutions. They repeatedly claimed that molecular biology would contribute to medicine, giving them an edge over natural historians and increasing their political appeal. French molecular biologist Jacques Monod (1910–1976), for example, argued in the 1960s that research in molecular biology deserved to be supported because it would allow the emergence of a new field called “molecular pathology.” At the same time, a number of these researchers distanced themselves from the clinic, preferring to carry out basic research in the laboratory. Yet the growing number of Nobel Prizes in physiology or medicine awarded to work in molecular biology (in 1962: Francis Crick, James Watson, and Maurice Wilkins; in 1965: François Jacob, André Lwoff, and Jacques Monod; in 1968: Robert W. Holley, Har Gobind Khorana, and Marshall W. Nirenberg; in 1969: Max Delbrück, Alfred Hershey, and Salvador Luria) seemed to vindicate their views of what counted as medical research.¹²

Conclusion

To a large extent, the rise of biomedicine in the twentieth century and its current organization rests on the division of labor and hierarchical relationship between the laboratory and the clinic envisioned by Pauling. But the development of medicine and especially of therapeutics has followed a much more complex path. Only recently have historians started to pay significant attention to the clinical research that goes into developing new therapeutics—not minimizing the importance of laboratory research but challenging that it represents a necessary starting point for medical research.¹³ Similarly, Pauling’s views about the simple relationship between genes and diseases has driven biomedical research, especially medical genetics, in the second half of the twentieth century. But it has also reinforced one of the most popular myths about the effect of genes on human health, disease, and behavior. As recent studies about human genomes indicate, for most common diseases, it is not one but many genes that are implicated. Furthermore, they don’t cause diseases, as the example of sickle-cell disease seemed to indicate; they only increase, and generally just slightly, the risk of occurrence of a disease. The simple world envisioned by Pauling has inspired biomedicine’s research agendas. Today, it has largely become a myth that often stands in the way of our understanding of the past, present, and future of health and disease.14