The FASEB Journal Essay

Discovery in the lab: Platos paradox and Delbru cks principle of limited sloppiness
Frederick Grinnell1
Department of Cell Biology, University of Texas Southwestern Medical School, Dallas, Texas, USA Towards the beginning of his book The Logic of Scientic Discovery, Sir Karl Popper reminds readers that there is no logic to how discoveries begin. The question how it happens that a new idea occurs to a manwhether it is a musical theme, a dramatic conict, or a scientic theorymay be of great interest to empirical psychology; but it is irrelevant to the logical analysis of scientic knowledge. This latter is concerned . . . only with questions of justication or validity (1). In short, the scientic method is a method to justify and validate new ideas, not a method by which new ideas can be generated. However, for those of us practicing science, generating new ideas (novelty) is central to what we hope to accomplish. We aim for new-search not re-search. It is new-search that advances our understanding of how the world works. Although in high demand, novelty also is hard to accomplish. Funding agencies hope to support creative, innovative research, but judging the potential for novelty is difcult. Consequently, review groups tend to focus instead on feasibilitythe likelihood of success in justication and validation of new ideas. The Greek philosopher Plato argued that true novelty is impossible to achieve. In the Dialogues, Plato has Meno ask Socrates: How will you look for it, Socrates, when you do not know at all what it is? How will you aim to search for something you do not know at all? If you should meet with it, how will you know that this is the thing that you did not know? And Socrates answers: I know what you want to say, Meno . . . that a man cannot search either for what he knows or for what he does not know. He cannot search for what he knowssince he knows it, there is no need to searchnor for what he does not know, for he does not know what to look for (2). The interchange above between Meno and Socrates Platos paradox helps explain just why discovery is so hard to accomplish. If a researcher seeks and nds what he already knows how to look for and recognize, then nothing new has been discovered. On the other hand, how can he look for what he does not know how to recognize? In practical terms, consider experimental design. Designing any experiment requires guessing what and when might be the outcome. Consequently, results inevitably will be biased in the direction of ones what and when expectations. We tend to nd precisely that for which we are looking.
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Max Delbru ck. Image courtesy National Library of Medicine

Aristotle dismissed the dilemma posed by Meno and argued in Book I of Posterior Analytics that, there is nothing to prevent a man in one sense knowing what he is learning, and in another not knowing it (3). As Michael Polanyi put it, we know more that we can tellthe tacit domain of knowledge (4). Discovery means getting in touch with that domain. Albert SzentGyo rgyi described this path to discovery as seeing what everybody else has seen and thinking what nobody else has thought. Rene Magrittes 1936 painting Perspicacity provides an artful example. The artist stares at a solitary egg resting on a draped table. On his canvas, he paints a bird in full ight.
1 Correspondence: Department of Cell Biology, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, TX 75390-9039, USA. E-mail: frederick.grinnell@utsouthwestern.edu doi: 10.1096/fj.09-0102ufm

The tacit domain of action precedes the tacit domain of knowledge. Think of world exploration. It is sometimes joked that Christopher Columbus did not know where he was going when he started out, did not know where he was when he got there, and did not know where hed been when he got back. Of course, Columbus thought he knew where he was going, where he had arrived, and where he had been. Only later, as he and others attempted to reproduce the voyages, did it become evident that his original assumptions and conclusions were awedthat he had discovered something different from that for which he had been searching. The fairytale of the Three Princes of Serendip tells a similar story. The princes father sent them on a mission. During their travels, they encountered many things for which they were not searching. Eighteenth-century writer Horace Walpole coined the word serendipity based on the story of the three princes (5). In science, researchers frequently do more than they intend. Max Delbru ck called this feature of science the principle of limited sloppiness (6). By sloppy Delbru ck did not mean meant careless or imprecise, although important ndings occasionally emerge through technical errors. Rather, Delbru ck was using the word sloppy in the rst sense listed in the Oxford English Dictionary: Very wet and splashy; covered with water or thin mud (5). Delbru ck emphasized that our conceptual understanding of a system under investigation always is somewhat muddy. Consequently, experimental design sometimes tests unintended questions as well as those questions explicitly under consideration. Unexpected results can emerge and lead to important ndings if the experimenter notices (7). The 1974 discovery of platelet-derived growth factor by Russell Ross, John Glomset and collaborators offers a classic example of the principle of limited sloppiness. The research group was investigating growth regulation of arterial smooth muscle cells. Their goal was to gain insight into the causes of focal accumulation of smooth muscle cells during atherosclerosis. Since the cells they were using were of monkey origin, the investigators prepared their cell culture medium with monkey serum. Everything was working smoothly until the director of the Regional Primate Center informed Glomset that the facility located in Eastern Washington no longer would provide the serum for the experiments. The investigators decided to prepare serum from animals that were housed in the monkey colony in Seattle. Since the same animals would be used more than once, it was desirable to minimize as much as possible the negative consequences of drawing blood from the monkeys. Therefore, before preparing serum, blood cells were removed from whole blood by centrifugation and returned to the animals. The remaining plasma was clotted to prepare serum. The new plan turned out to have a major awthe smooth muscle cells did not grow in medium prepared with the new
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serum. No one could gure out why not. Everyone assumed that technician error was responsible. Finally, Ross went into the laboratory to do the experiments himself. After he, too, was unable to get smooth muscle cells to replicate in medium containing serum prepared from monkey plasma, the laboratory began to focus on an alternative possibility: These ndings suggested that much of the growth promoting activity of the dialyzed blood serum was directly or indirectly associated with material released from blood cells during clotting (8). Experimental results can be thought of as pieces of a jigsaw puzzle. At the beginning of an experiment, the investigator has in mind a particular puzzle. The results usually t into that puzzle. However, each experimental result/puzzle piece can t into more than one puzzle. In the example above: Original puzzle: What factors regulate the growth of arterial smooth muscle cells cultured in serumsupplemented medium? Unexpected observation: Serum derived from clotted plasma does not promote cell growth. New puzzle: Do blood cells release factors during clotting that are required for growth of arterial smooth muscle cells? Once reconceptualized, the unexpected observation can be seen to answer a prediction or question based on the second puzzle instead of the rst. If one suspected that serum growth factors were released from blood cells during clotting, then comparing whole blood and plasma-derived serum would have been a direct way to test the idea. Charles Peirce recognized the signicance of unintended experiments for scientic discovery. He called this way of thinking abduction, as opposed to induction or deduction. According to Peirces formal description of abduction (paraphrased): An unexpected fact C is noticed. But C would be expected if A were the case. Consequently, there are grounds to investigate A (9). Abduction acts as a powerful general mechanism by which novelty enters research. Plato treated discovery as an event with two extremes: its one of them or I didnt notice anything, where? Those of us practicing science experience discovery as a process. As a process, additional possibilities arise something noticed but unrecognized, or something previously known but noticed in an unexpected place. Noticing the unexpected is key, but noticing is itself no trivial matter. Readers who want to test their skill of noticing the unexpected should look at Figure 1.2 in the 1955 paper by Wilson and Calvin describing the photosynthetic cycle (10). The gure diagrams the complex apparatus used for key experiments providing quantitative and time-dependent measurements of the process of photosynthesis. A comical element inserted in the diagram went unnoticed throughout the review and publication processes and, according to laboratory lore, was not noticed until many years later (11).
GRINNELL

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Almost one hundred and fty years ago, Claude Bernard one of the founders of modern biomedical researchwarned that inability to put aside previously accepted beliefs, at least temporarily, interferes with the ability of the researcher to notice anything more than the expected. Men who have excessive faith in their theories or ideas are not only ill prepared for making discoveries; they also make very poor observations. Of necessity, they observe with a preconceived idea, and when they devise an experiment, they can see, in its results, only a conrmation of their theory. In this way they distort observations and often neglect very important facts because they do not further their aim (12). Following Bernards warning, we can conclude that there may not be a method of discovery, but there is a clear strategy be prepared to notice the unexpected. Nothing noticednovelty lost.
Author notes: The ideas in this essay can be found discussed in greater detail in the authors new book Everyday Practice of Science: Where Intuition and Passion Meet Objectivity and Logic, Oxford University Press, 2009. The author heard the PDGF discovery story from Russell Ross in 1985. In preparation of this essay, additional details and conrmation of the story were obtained from John Glomset, Dan Bowen-Pope, Joe Leibovich, and Elaine Raines.

REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. Popper, K. R. (1959) The Logic of Scientic Discovery, Basic Books Inc., New York Plato (380 BCE) Meno. Internet Classics Archive, http://classics. mit.edu/Plato/meno.html. Accessed October 2008 Aristotle (350 BCE) Posterior Analytics, Book I. Internet Classics Archive, http://classics.mit.edu/Aristotle/posterior.html. Accessed October 2008 Polanyi, M. (1983) The Tacit Dimension, Peter Smith Publishers, Gloucester, Massachusetts Oxford English Dictionary Online (1989). Oxford University Press, http://dictionary.oed.com. Accessed October 2008 Hayes, W. (1982) Max Ludwig Henning Delbruck. Biographical Memoirs of the Fellows of the Royal Society 28, 58 90 Dulbecco, R. (January 14,1999) Phone interview between the author and R. Dulbecco regarding the meaning of Delbru cks principle Ross, R., Glomset, J., Kariya, B., and Harker, L. (1974) A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc. Natl. Acad. Sci. USA. 71, 12071210 Peirce, C. P. (19311958) Harvard Lectures on Pragmatism (1903). In: Collected Papers of Charles Sanders Peirce. (Hartshorne, C., Weiss, P., and Burks, A., eds.) Vol. 5, pp. 188 189, Harvard University Press, Cambridge Wilson, A. T., and Calvin, M. (1955) The photosynthetic cycle: CO2 dependent transitions. J. Amer. Chem. Soc. 77, 5948 5957 Grinnell, F. (2009) Everyday Practice of Science: Where Intuition and Passion Meet Objectivity and Logic. Oxford University Press, New York Bernard, C. (1957) An Introduction to the Study of Experimental Medicine (1865), Dover Publications, Inc., New York

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10. 11. 12.

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CKS PRINCIPLE OF LIMITED SLOPPINESS DISCOVERY IN THE LAB: PLATOS PARADOX AND DELBRU 9