By Daniel Tarade
The Nobel Prize is inarguably the most prestigious honour that can be bestowed upon a scientist – whether it be in medicine and physiology, chemistry, or physics. Ignoring the biases and flaws inherent with such an award, discoveries honoured with a Nobel Prize can be reasonably assumed to represent the greatest scientific achievements of the past century, give or take. When one peruses the list of past prizes, one might assume that they will more often than not be reminded of the scientific discoveries that changed how we think about the world – or rather, how scientists in a particular discipline engage with their science. That is not necessarily the case.
Revolutionary science, as written by Thomas Kuhn, is that which establishes a paradigm or otherwise overthrows a previously held paradigm. Kuhn draws the distinction between revolutionary science and the scientific program that springs from the revolution – that is to say the normal science that accounts for the majority of scientific endeavours. Normal science aims to elaborate, extend, and clarify paradigms but does not intentionally aim to topple a paradigm, although Kuhn astutely notes that paradigm shifts somewhat inevitably arise from the normal science program as odd observations continue to pile up and the usefulness of a prior paradigm to account for these observations evaporates. Important to note, Kuhn aimed to describe how science is done and largely avoided prescriptive claims regarding the relative importance of revolutionary and normal science.
Is the Nobel Committee biased towards revolutionary research? I would argue not. For instance, Albert Einstein won a Nobel Prize in Physics for his work on the photoelectric effect and not for his work on general relativity, a truly revolutionary concept. An example from medicine and physiology, an area I am more comfortable discussing, centers on DNA as the molecular, chemical carrier of genes. Oswald Avery, a Canadian scientist working at Rockefeller Institute, worked meticulously for 15 years to show that Pneumococcus could be 'transformed' by DNA. Of course, the corollary was that genes were made up of DNA. His 1944 publication,[i] along with Colin MacLeod and Maclyn McCarty, has been described as the most important publication of the 20th century, in regards to physiology or medicine. It also ushered a proper paradigm shift, with the prevailing notion of genes being proteinaceous in nature giving way to the importance of DNA as the substance of genes. It is the revolutionary nature of the work that impeded its recognition by the Nobel Committee, at least partially. To award a Nobel Prize is to endorse the conclusions. With a revolutionary work, the cautious approach is to wait for the community to endorse the paradigm, as evidenced by a resulting normal science program. Unfortunately, Avery was already a professor emeritus when he published his seminal discoveries and passed away in 1955 before he could be recognized with the greatest prize in science. His impact on science, however, lives on, as evidenced by the many discoveries in genetics and cell biology that spring from the paradigm he and his team brought forth, many of which were recognized by a Nobel Prize. See postscript for additional reading material regarding other biases that may have worked towards this notable exclusion.
In reality, there is a non-insignificant number of Nobel prizes awarded for what can be best described as normal science. How does a ‘mere’ elaboration, extension, or clarification merit such recognition? Kuhn did tackle this conundrum but from a different perspective. He was interested in why scientists seem to tackle the problems of normal science with such aplomb when, often enough, the results are accurately pre-empted and forecast. What Kuhn describes in an attempt to explain this phenomenon is that scientists hold an incredible appreciation for puzzle solving.[ii] Such an assertion does not need much justification. It only requires the briefest of exposures to a gaggle of scientists discussing their work amongst one another. Yes, the hypotheses and models are discussed at length. But perhaps even more so, conversation centers on the methods by which they have come to their conclusions; the elegant experimental design, subtle tweaks of protocol, or ambitious, well-controlled, and meticulous observation. Scientists appreciate the creative process. A common-enough complaint is that work lacks creativity, laconically described as a fishing expedition. So, while a Nobel Prize might be awarded for paradigm-shifting work, I contend that the greatest honour of science may also befall those who tackled known problems and obtained results that were entirely compatible with existing paradigms. This latter group were worthy of such recognition because of the creativity and effort that became synonymous with their work. To explore this idea, the work of Dr. Paul Ehrlich is incredibly illuminating. Dr. Ehrlich was awarded a Nobel Prize but no fewer than seven Nobel Prizes were awarded for discoveries that emerged from the incredibly efficient program of normal science that emerged in the wake of Dr. Ehrlich’s revolutionary work. Just as Kuhn notes, normal science is not less than but merely different from revolutionary science.
Paul Ehrlich began his scientific career fully entrenched in a normal science program. As a young medical student, Ehrlich tasked himself with screening various industrial dyes for the staining of human tissue.[iii] It is hard to imagine the revolution that emerged. At most, it was expected that Ehrlich would be able to re-purpose a dye for a clinical application; a tool for making tissues easier to observe under a microscope. However, Ehrlich soon observed that certain dyes preferentially stain certain cellular structures. Such an observation may not seem that incredible but in fact, was absolutely crucial for the emergence and development of the fields of chemotherapy and medicinal chemistry. That a chemical might specifically interact with a nuclei or granule morphed into the idea that a chemical might specifically interact with a bacterium or cancer cell. This hypothesis was tested thoroughly by Ehrlich. In 1910, his lab outlined their discovery and optimisation of the anti-syphilitic drug, Salvarsan. Their efforts in discovering an anti-syphilitic drug underlies the basis of medicinal chemistry and remains a powerful approach to discovering new medicinally active compounds. Ultimately, Ehrlich was the pioneer of the “silver-bullet concept,” which plainly states that drugs with specific affinity for all sorts of cells, including those of malignant origin, exist and can be used to cure all manner of disease. Thus, chemotherapy was born and its original paradigm, brought forth by Ehrlich, stands to this day.
As a brief sojourn, if the work and ideas of Paul Ehrlich are representative of revolutionary science, than the following discoveries, fully encapsulated within the paradigm Ehrlich brought forth, are examples of normal science; The 1939 Nobel Prize in physiology and medicine, awarded to Gerhard Domagk, "for the discovery of the antibacterial effects of prontosil" (a dye no less); The 1945 Nobel Prize in physiology and medicine, awarded to Sir Alexander Fleming, Ernst Boris Chain, and Sir Howard Walter Florey, "for the discovery of penicillin and its curative effect in various infectious diseases"; The 1948 Nobel Prize in physiology or medicine, awarded to Paul Hermann Müller, "for his discovery of the high efficiency of DDT as a contact poison against several arthropods" (started his career working with dyes); The 1952 Nobel Prize in physiology and medicine, awarded to Selman Abraham Waksman, "for his discovery of streptomycin, the first antibiotic effective against tuberculosis"; The 1957 Nobel Prize in physiology and medicine, awarded to Daniel Bovet, "for his discoveries relating to synthetic compounds that inhibit the action of certain body substances, and especially their action on the vascular system and the skeletal muscles"; The 1988 Nobel Prize in physiology and medicine, awarded to Sir James W. Black, Gertrude B. Elion, and George H. Hitchings, "for their discoveries of important principles for drug treatment"; The 2015 Nobel Prize in physiology and medicine, awarded to William C. Campbell and Satoshi Ōmura, "for their discoveries concerning a novel therapy against infections caused by roundworm parasites" and Youyou Tu, "for her discoveries concerning a novel therapy against Malaria."
When reading the press release for the 2015 Nobel Prize, the puzzle-solving aspects of the work is readily appreciated. For example, Satoshi Ōmura is described as being “equipped with extraordinary skills in developing unique methods for large-scale culturing and characterization of … bacteria,” which was necessary for identifying Streptomyces cultures with biological activity against roundworm parasites. Black, Elion, and Hitchings (1988 Nobel Prize) were specifically recognized for their work on drug development because “they introduced a more rational approach based on the understanding of basic biochemical and physiological processes.” That is to say, they were recognized because of their approach to science but not for discoveries that revolutionized, in a Kuhn-ian sense, their field. Rather, Elion and Hitchings, for example, identified differences between nucleic acid metabolism among different organisms and designed ‘silver-bullets’ that exploited that difference. Their research resulted in effective treatments for leukemia, autoimmune disorders, herpes, and HIV/AIDS. Importantly, their approach is clear extension of Ehrlich’s ideas, who himself recognized that to design a ‘silver-bullet’ one had to first understand the differences between what is to be eradicated and what is to be spared.
So does winning the Nobel Prize necessitate excellence in puzzle-solving? In reality, puzzle-solving is not a requirement of the prize and the standards appear to fluctuate. Much less has been written about Gerhard Domagk, when compared with Ehrlich, despite also discovering an antibiotic by screening thousands of chemical dyes. Having made his discovery (Prontosil) in 1932, it was harder to appreciate the puzzle-solving of Domagk when a similar program was conducted by Ehrlich over twenty years earlier. However, the discovery of another effective antimicrobial was an important validation of the 'silver-bullet' paradigm and of obvious societal value that seemingly deserved a Nobel Prize.[iv] However, as time passes the threshold for awarding a Nobel Prize on the basis of societal value appears to increase. One Nobel Prize has been awarded to research on poliomyelitis. It was not awarded to Jonas Salk. The Nobel Prize in Physiology or Medicine 1954 was awarded jointly to John Franklin Enders, Thomas Huckle Weller and Frederick Chapman Robbins "for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue." Awarded just a year prior to the immensely successful field trial of the polio vaccine developed in the lab of Jonas Salk, the public at large thought it was inevitable that Salk himself would be recognized in due time. However, the scientific community did not share the same idea. The development of a vaccine, regardless of how beneficial to society, was thought to be akin to following a recipe and lacked creativity.[v] So why were Enders, Weller, and Robbins worthy? Their discovery was revolutionary in the sense that they established a technique for growing virus easily under cell culture conditions, which made the work of Salk possible. Perhaps a discussion for another day, but Kuhn does also discuss revolutions as springing from the development of new techniques and methods. If the development of a polio vaccine does not merit a Nobel Prize, than it is clear that having a revolutionary impact on societal health is not sufficient. It is also clear that solving a problem creatively or even beautifully is somewhat important.
It may be tempting to conflate the Nobel Prize with revolutionary science. Of course, penicillin was revolutionary. But in a scientific sense, this discovery was anticipated many years earlier. Normal science does not mean that the research is boring or unimportant. Kuhn recognized the exciting puzzle-solving aspects that can underly normal science. Although revolutionary science is enthralling for the avalanche of new possibilities, applications, and hypotheses, it requires the normal science program for the application of these discoveries to benefit human health.
Transformation is the process by which bacteria take up DNA from their surroundings. The experiments conducted by Avery and colleagues focused on the transformation of non-virulent pneumococcus lacking a sugar capsid to a virulent, encapsulated form when incubated with extract of heat-killed virulent pneumococcus. During the 15 years that Oswald Avery worked on discovering the chemical nature of the transforming principal, work that he himself conducted on the bench, he endured a publication dry-spell of seven years!
Ehrlich's concept of specificity was also extended in his “side-chain theory of immunity” in which he argues, by analogy, that perhaps the specific binding of an anti-toxin to a toxin mimics what occurs at the immunological level within an organism (i.e. immune cells recognizing antigens via antibodies).
Gertrude B. Elion and Youyou Tu are both exceptions when it comes to the Nobel Prize for physiology of medicine. Elion was the first individual to win the award without having obtained a PhD or a medical degree. Tu is the second such individual. However, Tu had not even obtained a Master’s degree. Two incredible women and two incredible scientists!
[i] Avery, O. T., MacLeod, C. M., & McCarty, M. A. (1979). Studies on the chemical nature of the substance inducing transformation of pneumococcal types. Inductions of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. Journal of Experimental Medicine, 149(2), 297-326. 35th anniversary, reprint. [a] For a narrative on Oswald Avery's revolutionary work on the transforming principal, see Barry. (2004). The great influenza: the epic story of the deadliest plague in history, Viking. [b] For a discussion about why Avery and his team were not recognized by the Nobel Committee, see Reichard, P. (2002). Osvald T. Avery and the Nobel prize in medicine. Journal of Biological Chemistry, 277(16), 13355-13362.
[ii] Kuhn. (1962). The structure of scientific revolutions, University of Chicago Press. See chapter IV, "Normal Science as Puzzle-solving."
[iii] Mukherjee. (2010). The emperor of all maladies: A biography of cancer, Scribner. See chapter "Dyeing and Dying."
[iv] Bosch, F., & Rosich, L. (2008). The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize. Pharmacology, 82(3), 171-179. Of course, the work of Gerhard Domagk is best contextualized via veneration of Paul Ehrlich.
[v] Kluger. (2004). Splendid solution: Jonas salk and the conquest of polio, G.P. Putnam's Sons.