Individual science fiction stories may seem as trivial as ever to the blinder critics and philosophers of today – but the core of science fiction, its essence, has become crucial to our salvation if we are to be saved at all.
-Isaac Asimov

Fundamentals of Immunology, 3rd edition, 1956. By William C. Boyd.
Fundamentals of Immunology, 3rd edition, 1956. By William C. Boyd.

Nineteen fifty six was an eventful year; Heartbreak Hotel entered the US music charts, the Suez Canal crises erupted, the hard disk drive was invented by IBM and William C. Boyd’s Fundamentals of Immunology (3rd ed.) was published. This classic immunology textbook covered everything from blood typing and immunity to infection and antibodies, and even atopic allergy in bottle-fed baby walruses. With hindsight on our side, Fundamentals reads like fantastic science fiction, full of opinionated and poetical prose that is characteristically absent from modern scientific writing. As readers from the future, we have an almost omniscient perspective on past scientific ‘truths’. In Fundamentals, William C. Boyd proselytizes many immunological theories that are so perplexingly wrong from a modern scientific perspective, they seem to have been concocted from the mind of Asimov, not from the famous scientists accredited to their discovery such as Burnett, Medawar, Ehrlich and Freund. Despite making a few poor predictions, many of the theories Boyd supported would only become accepted decades after Fundamentals was published. Let us begin with William C. Boyd.

Dr. William C. Boyd: A champion of racial equality
Boyd was a professor of immunochemistry at Boston University, a linguist and an avid mushroom collector. As an immunologist, Boyd discovered that blood groupings were heritable and that certain carbohydrates in plants seemed to have antibody-like specificity, which he called lectins. On top of this, Boyd was a humanist; he championed racial equality through science and travelled the world to characterize race, based on blood typing to which he concluded there was no “superior race”. An impressive feat given the 1950’s are synonymous with segregation and the civil rights movement. On top of these achievements, Boyd was an eloquent writer, as evident throughout the chapters of Fundamentals.

Immunology then and now
The phantasmagoric introduction of Fundamentals starts out with a lofty, yet simple sentence: “The beginnings of our subject go back to the origin of life itself.” Boyd explains through prose how competition driven-evolution of the immune system from the beginning of life itself, led to the development of immunity as a means for an organism to protect itself from being prey. In the climax of the introduction, Boyd defines immunology, a nascent field at the time, as being the study of both the mechanisms by which resistance to infection is increased and how excessive responses can be detrimental in the form of hypersensitivity and autoimmunity.

The textbook continues in a familiar somber, scientific tone to tackle major concepts of the era’s immunology, although paragraphs are constantly interjected with the author’s opinions.  Antibodies are heavily featured with about half the book dedicated to the intricacies of antibody-antigen interactions. In fact the term antibody was still young; a lexicon existed to describe antibodies in a context-dependent manner, including opsonins, amboceptor, bacteriotropin, precipitin and hemolysin. If antibodies were not the immunological answer, the phagocytes were. Lymphocytes were noted once or twice as minor observations, but played no role in the understanding of immunology at the time. However, the importance of lymphocytes was foreshadowed: “immunity to certain other diseases may persist for years after all detectable traces of antibody have disappeared.”

Unlike modern textbooks which don’t criticize the shortcomings of our scientific knowledge, Boyd openly laments the roadblocks to understanding immunology in the 1950s. Some of the dilemmas of the era seem silly to us. For example, it was unknown what cell was responsible for antibody production, with the best guess being plasma cells as their number closely correlated to antibody production, yet these cells were far from being irrefutably identified as the antibody producing cell. On the other hand, many barricades to progress in immunology continue to stymie research today. Mast cells were described as readily observable, but mysterious and misunderstood. Further to this, Boyd states; “part of the difficulty [in understanding the immune system] is the lack of precise differentiation of various types of cells and their genesis.” There is not a single immunologist who would debate this as fact today.

How did they conclude that?
Much of the immunology in Fundamentals has stood the test of time, but many theories were just plain wrong; making for amusing reading. Hypotheses on the characteristics of antibodies are a prime example. Scientists had accurately identified the size of antibodies as 270 angstroms, by measuring the gap between opsonized erythrocytes and phagocytes in electron micrographs. They were also not far off identifying the valency of antibodies with low molecular weight as two, and high molecular weight as 10-12 through enzymatic digestion. Scientists were however somewhat off on the structure of antibodies based on complex frictional ratios and relaxation times in fluidic models, with leading immunologists safely presuming antibodies were likely non-symmetrical, cigar-like ellipsoids.

Protein replication and antibody diversity circa 1956.
Click to view a larger version.

The replication of antibodies and the generation of antibody diversity, or specifically how random “new” proteins were generated during an immune response were fiercely debated in the 1950s. In this pre-Watson and Crick era, the units of inheritance were presumed to be proteins based on the diversity of amino acids versus the uniformity of nucleic acids. Mechanistically this hypothesis made sense in that a protein could act as its own template when stretched out into a monomolecular strand to provide access for incoming amino acids. It was presumed that nucleic acid, often observed in contact with protein, was simply there to keep the template protein in an unfolded state. This hypothesis in itself led to a contradiction; how was antibody diversity generated from flawless replication of template protein? The dominant hypothesis, proposed by Haurowitz, was that diversity arose from the antigen interacting directly with template protein, thus changing its shape and slightly altering the copying fidelity to generate antibody variants. Burnett challenged this hypothesis based on its inability to explain the recall response of antibodies in the absence of antigen. Yet, Burnett’s improved hypothesis was increasingly complex, and equally as far-fetched. He stated that a dual-functioning and long-lived antibody educating enzyme, could have its structure irreversibly altered when it degraded antigen, thus maintaining memory in the absence of the antigen.

Nailed it: Immunological prophecies
When shooting in the dark, you are bound to hit something. Indeed Boyd and colleagues got a number of things right, such as the description of adjuvants, a genetic basis for histocompatibility and the classical pathway of complement activation. Other hypotheses would take half a century to prove. Boyd proclaimed, “the first sequence of responses which constitute inflammation is a wave of destruction of cells,” indicating that scientists of the 1950’s were already thinking about innate danger signals. Furthermore, in a discussion on cholera toxin’s ability to permeabilize non-immune cells, but not immune cells in the intestine, it was reasoned that resident non-immune cells could not acquire immunity. Fundamentals took the discussion one step further by claiming that the acquired immunity of intestinal immune cells, such as macrophages, was likely to be acquired through intracellular antibodies. This was spot on with the recent discovery of the intracellular antibody receptor, TRIM21. Concerning atopy and hypersensitivity, Boyd discussed the documentation of parasitic infection causing the exacerbation of allergy whilst bacterial infection promotes delayed-type hypersensitivity. Even though the Th1/Th2 paradigm was a long way off, it was clear that there was some polarization of the immune system against pathogens.

In summary, Fundamentals of Immunology, which encapsulates the immunology of its time, is eloquently written and reads like science fiction. This comes as little surprise; Boyd, in addition to being an immunologist was also a science fiction writer and long-time friend of Asimov. As a matter of fact, the two even published a book together, Races and People, based on Boyd’s research into race and blood typing. No doubt this friendship influenced Boyd’s science and Asimov’s fiction. After reading Fundamentals from a historical perspective, one is left wondering: in 60 years’ time, which of our immunological hypotheses will be laughed at, and which will be revered?


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Eric Gracey

Contributing Editor
Eric is a PhD student with the Department of Immunology at the University of Toronto. He did his undergraduate degree at the University of Auckland, New Zealand where he investigated the effects of diet on gout. He currently studies the role of the immune system in arthritis, specifically an arthritis of the spine called ankylosing spondylitis. When not in the lab, Eric likes to run and has taken up backcountry canoeing.

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