As scientists, we love to answer questions. It’s part and parcel of the job description. Conveniently, nature offers up plenty of complex questions, just waiting for us to validate, demonstrate, and elucidate our way to the answer. And when we are really quite sure that we understand something about the world, we give it a name – “The Copernican principle”, “Newton’s laws of motion”, or for us immunologists, “Burnet’s clonal selection theory”. Yet history has taught us that even the most widely respected scientific theories have limited lifespans; they become outmoded as new, more attractive ideas take their place.
Philosopher scientist Thomas Kuhn conceptualized the turnover of scientific ideas in his landmark book, The Structure of Scientific Revolutions (1962), wherein he suggested that scientific practice transitions between periods of “revolutionary” and “normal” research. For Kuhn, moments of genuine inspiration only occur during the revolutionary phases that can spawn new ways of thinking. During periods of normal science, everyday researchers like you or me, who operate in a specific conceptual framework he termed a “paradigm”, are performing research that is akin to a puzzle-solver filling in the last few numbers of a Sudoku. Although as a physicist, Thomas Kuhn never got the chance to appreciate a puzzle as extravagant as the design of a 12-colour flow panel.
Scientific communities at the time took great exception to Kuhn’s controversial definitions – what self-respecting scientist could stomach being told that their cutting-edge research is merely “normal”? Yet Kuhn argued that the impetus for change within a paradigm is only triggered when experimental or theoretical anomalies accumulate to a critical mass. These scientific revolutions spark a rewriting of the rules, the infamous “paradigm shift”, that sets the foundations for another period of bread-and-butter, normal science. Now overused, and often incorrectly at that (you can blame the economists), the term “paradigm shift” was most relevant when used to describe revolutions in more fundamental scientific disciplines– a prime example being the transition from Newtonian to Einsteinian physics once relativity was established. But how appropriate is the definition to the more youthful, multidisciplinary field of immunology?
Immunology’s Identity Crisis
One could consider the early days of immunology as little more than curious diversions from the more established research disciplines. Variolation and vaccination were medical innovations designed with the primary goal of curbing the rampant scourge of smallpox and other diseases. The discovery of factors that could transfer immune protection, such as complement and antibodies, was the work of biochemists working off on a tangent. It could be said that immunology as a field didn’t warrant a paradigm of its own until the establishment of a “humoralist” camp comprised of the scientific descendants of Emil Von Behring, who discovered the diphtheria antitoxin (antiserum) in the late 19th century. Humoral immunity at the turn of the 20th century was as fashionable as the microbiome is today. This period of what Kuhn would describe as “puzzle-solving normal science” continued until the 1940s, when cracks in the framework of the humoral paradigm began to accumulate.
The first challenges to humoral immunity emerged when scientists realized that certain phenomena could not be attributed to the presence of antibodies alone, a chief example being allograft rejection. The death blow to the hegemony held by the humoral immune paradigm came in the form of the seminal cell transfer experiments by Karl Landsteiner and Merrill Chase. Landsteiner and Chase injected both cells and serum from M. tuberculosis challenged guinea pigs into naïve ones and upon secondary exposure, observed that immune protection was only granted to animals that were given the cellular fraction. These paradigm-shifting experiments humbled the humoral immunologists and forced them to at least acknowledge the existence of a second arm of the immune system mediated by cells. On Chase’s discovery, his Rockefeller colleague Ralph Steinman once mentioned, “People never anticipated that there would be something other than antibodies. It was an amazing finding.”
The Clonal Revolution
Although it was all well and good to know that both cells and antibodies contributed to immunity, researchers of the time remained perplexed with the problem of specificity. More precisely, how could the immune system account for the near infinite number of different antigens that a host could encounter? The short answer was the clonal selection theory. Now attributed to Frank Macfarlane Burnet, this theoretical masterwork required the input of three men: Burnet himself, David Talmage and Niels Jerne. In 1957, Burnet published his then-hypothesis in a succinct paper of just two pages with no data figures (try pulling that off now) explaining how the immune system applied a cycle of cell division, mutation, and selection to form a broad diversity of clonal specificities.
Much like any revolutionary scientific theory, clonal selection immediately divided opinion and required experimental validation to convince the numerous naysayers. It was not a long wait; just a year after its publication, Gustav Nossal and Joshua Lederberg set out to challenge the most controversial of clonal selection’s postulates – that clonal cells produced antibody of a single specificity. Nossal and Lederberg immunized rats with two different strains of Salmonella and used the latest in microbiology techniques – single cell microculture on mineral oil – to check the reactivity of the antibodies produced. Not a single cell out of 500 showed dual reactivity to both strains, confirming “one cell, one specificity.” Following validation, the clonal selection theory provided the robust theoretical basis that distinguished immunology as its own field of research. It put to bed competing instructional or selective mechanisms of antibody receptor specificity and shifted immunology from its biochemical origins to a fresh and exciting cell biology of “self/non self-recognition.”
A Tough Act to Follow
A significant number of immunology discoveries of the last 60 years – T-cell/MHC restriction, antigen receptor rearrangement, immunological tolerance and memory, to mention a few – were discovered within the framework of the clonal selection paradigm. Its influential shadow looms as large for immunology research today as it did in the 1960s.
That’s not to say that the field stood still in the meantime. Other paradigms have shared the spotlight with clonal selection – some with lasting impact, others less so. In the 1970s and 1980s, Niels Jerne turned immunology inside out by promoting his immune (idiotype) network theory, which argued that the individual components of the immune system – cells, antibodies, other soluble factors –recognize, bind, and communicate with each other, not just with foreign material, to coordinate complex responses against disease. Yet this revolution was not to be, as the global immunology community dismissed the network theory when a search for the master regulatory gene during the 1980s came up empty-handed. Jerne actually shared the 1984 Nobel Prize in Physiology or Medicine specifically for this theory; unofficially, he won it for his theoretical genius and a lifetime of scientific contributions.
To look at another example, Charles Janeway is rightfully referred to as the godfather of innate immunity, as it was he who recognized in 1989 that research on the clonal selection paradigm, effectively adaptive immunity, was “approaching the asymptote” – the title of his famous address to a Cold Spring Harbor symposium – with respect to genuinely new ideas. His prediction formed the basis for a new field of innate immunity that was based on recognition of non-clonal patterns found on pathogens. Although taken for granted today as canon, Janeway’s radical thinking took years to accept by a community so entrenched in lymphocyte research in the light of the clonal selection paradigm.
A Time for Change
As Kuhn predicted, each and every one of these immunological paradigm shifts brought on a period of incredibly productive science, as researchers could apply the latest in technological approaches within a new set of principles. Equipped in this day and age with an arsenal of powerful bioinformatics and big data resources, we really do generate more information than we know what to do with.
So are we on the verge of figuring out the immune system? Despite recent advances like ILCs, NKTs, and regulatory Bs, the answer is firmly no. Why is it so difficult to generate a protective immune response against some pathogens like HIV? How is the immune system regulated by the brain? Why can’t we treat allergies prophylactically? Can the existing framework of immunology provide the answer to these questions and more? If not, is there a Burnet, Jerne, or Janeway of this generation that has the ingenuity and more importantly, the guts, to point us in a new direction?
- Andersson, U., and K. J. Tracey. 2012. “Neural reflexes in inflammation and immunity.” J Exp Med 209 (6):1057-68. doi: 10.1084/jem.20120571.
- Atlan, Henri. 1998. “Paradigms in Immunology and Modern, Post-Modern, Post-Post-Modern.” Biology and Philosophy 13 (1):125-131.
- Baxter, A. G., and P. D. Hodgkin. 2002. “Activation rules: the two-signal theories of immune activation.” Nat Rev Immunol 2 (6):439-46. doi: 10.1038/nri823.
- Eichmann, Klaus. 2008. The Network Collective: Rise and Fall of a Scientific Paradigm. Basel, Switzerland: Birkhäuser Verlag.
- Gitlin, A. D., and M. C. Nussenzweig. 2015. “Immunology: Fifty years of B lymphocytes.” Nature 517 (7533):139-41. doi: 10.1038/517139a.
- Greenberg, Steven. A Concise History of Immunology. 15.
- Hodgkin, P. D., W. R. Heath, and A. G. Baxter. 2007. “The clonal selection theory: 50 years since the revolution.” Nat Immunol 8 (10):1019-26. doi: 10.1038/ni1007-1019.
- Janeway, C. A., Jr. 1989. “Approaching the asymptote? Evolution and revolution in immunology.” Cold Spring Harb Symp Quant Biol 54 Pt 1:1-13.
- Kaufmann, S. H. 2008. “Immunology’s foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff.” Nat Immunol 9 (7):705-12. doi: 10.1038/ni0708-705.
- Kuhn, Thomas S. 1996. The Structure of Scientific Revolutions: University Of Chicago Press.
- Medzhitov, R. 2009. “Approaching the asymptote: 20 years later.” Immunity 30 (6):766-75. doi: 10.1016/j.immuni.2009.06.004.
- Medzhitov, R., et al. 2011. “Highlights of 10 years of immunology in Nature Reviews Immunology.” Nat Rev Immunol 11 (10):693-702. doi: 10.1038/nri3063.
- Naughton, John. 2012. “Thomas Kuhn: the man who changed the way the world looked at science.” The Guardian, 5. https://www.theguardian.com/science/2012/aug/19/thomas-kuhn-structure-scientific-revolutions
- Nossal, G. J. 2002. “One cell, one antibody: prelude and aftermath.” Immunol Rev 185:15-23.
- O’Connor, Anahad. 2004. “Merrill W. Chase, 98, Scientist Who Advanced Immunology.” The New York Times, Jan 22, 2004.
- Parish, C. R. 2003. “Cancer immunotherapy: the past, the present and the future.” Immunol Cell Biol 81 (2):106-13. doi: 10.1046/j.0818-9641.2003.01151.x.
- Pradeu, Thomas. 2012. The Limits of the Self: Immunology and Biological Identity: Oxford University Press.
- Sankaran, Neeraja. 2012. “The Pluripotent History of Immunology.” AVANT 3 (1):37-54.
- Soderqvist, T. 2002. “The life and work of Niels Kaj Jerne as a source of ethical reflection.” Scand J Immunol 55 (6):539-45.
- Tauber, A. I. 2003. “Metchnikoff and the phagocytosis theory.” Nat Rev Mol Cell Biol 4 (11):897-901. doi: 10.1038/nrm1244.
- Viret, C., and W. Gurr. 2009. “The origin of the “one cell-one antibody” rule.” J Immunol 182 (3):1229-30.
- Wabl, Matthias. 2012. A Witness of a Revolution in Immunology.
- Weissman, I. 2010. “Lymphocytes, Jim Gowans and in vivo veritas.” Nat Immunol 11 (12):1073-5. doi: 10.1038/ni1210-1073.
Latest posts by Michael Le (see all)
- Revolutions in Immunology - June 13, 2016
- Driven By Discovery: Alumni Interview with Brad Jones - September 27, 2015
- Controlling CRISPR - March 30, 2015