Interaction between History of Science and Automatic Computational Discovery: a Two-way Road

Pio Garcia1
1School of Philosophy National University of Cordoba, Argentine pio@ffyh.unc.edu.ar

Abstract. In this paper we present the case of Krebss discovery as an example of how could be reconsidered the relationship between cognitive science and history of science. Usually the history of science is used as a datas source for computer simulations. But we present some evidence that suggest that some studies in cognitive science could change our ways to read history of science. In this way, we rebuild the original problem. It is no more a problem about how to simulate a human being from historical data; it is now the task of how to understand scientific creativity. The source for this understanding has two faces: one of them is historical and the other one is computational and psychological.

Introduction
To simulate human beings with machines is a dream with a long story. However, with digital computers, this dream takes a more definite form, especially with the beginning of cognitive revolution computers plus cognitive psychology- . An important goal of cognitive sciences is to use computational simulations as a tool to understand human problem solving. The pioneering work of Herbert Simon and their collaborators have been one of the most outstanding in this field. However, those simulations have been criticized, because they have been considered too simple and schematic to meet the complexity of real scientific practices. In order to reply those critics, Simon and Kulkarni developed a computational simulation: KEKADA. This computer program simulates Krebss discovery of the cycle of the ornithine. Simon and Kulkarni choose this case because there has been a detailed historical account by Frederick Holmes [7], [8], [9]. In this sense, KEKADA can be considered one of the greatest attempt of simulate scientists creativity. Grahoff and May, continuing with this research path, tried to improve this recon1

1 Herbert Simon defines cognitive science as computer simulations plus cognitive psychology. In the rest of this paper, we will use the expression cognitive science with this meaning.

struction with another computer simulation: CDP [5]. We will argue that both simulations fall short in some important ways and, more important, this task is always performed in one direction: from historical account to computer simulation. Indeed, can our scientific practices learn something from computer simulations? In this paper we try to answer this question in an affirmative way, at least from an historical point of view. Therefore, we pursuit two main task. First, we criticize the computer simulations of Krebss discovery. Second, we propose another way to see the interaction between historical accounts and cognitive sciences. We present evidence that suggest that the cognitive science could have some impact in understanding the history of science. In this way, we rebuild the original problem. It is no more a problem about how to simulate a human being; it is now the task of how to understand scientific creativity. The source for this understanding has two faces: one of them is historical and the other one is computational and psychological. To achieve those goals we present first a brief account of Krebss discovery, and then we summarize the computational simulations of this discovery. Later, we will present some critics and enhancements to those simulations. We will use the familiar concept of problem space to organize our proposal. Finally, we present some evidence that cognitive science could complement our readings of history of science.
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Krebss Discovery
The discovery of the cycle of the ornithine was the first demonstration of the existence of a cycle in the metabolic biochemistry and it marked a new stadium in the development of the biochemical thought [7]. The problem that Krebs approached had been studied by several years with few results . With some fragmentary knowledge, Krebs began its investigations about the process of the synthesis of the urea. In Otto Warburg's laboratory, between 1926 and 1930, Krebs learned a method that the same Warburg had developed. This method consisted on studying reactions in "slices of tissue instead of making it in the same organ .
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2 We have presented some of these ideas in an earlier and shorter version of the current paper [6]. 3 In the XIX century, Friedrich Whler had synthesized the urea in laboratory [14]. The urea was the first organic substance synthesized in a laboratory. This result had led to some hypotheses about how the synthesis would be in vivo. The study of the intermediate metabolism begins to be developed by the middle of the XIX century, since until then an input-output" concept reigned in the theoretical and experimental physiology [4]. In other words, the investigation was centered in the study of the initial and final products, not in the intermediaries. Several scientists of the time said that "only chemistry could give an answer to the problem of the intermediate metabolism [4] p.361. 4 The method used until then was called "perfusion". In accordance with this last method, it was provided blood to the organ to study in an artificial way - generally of some individual of the same species or with similar characteristics - to maintain it under conditions near to the

Krebs begins with the idea of applying this method to the study of the synthesis of the urea. This way, Krebs tries to use this method with several amino acids without success. When he carried out experiments with ornithine - one of the less common amino acids - and ammonia, unexpectedly big quantities of urea take place. This determines that their study centered in the called "ornithine effect". The strategy in this point was the standard one: if a certain compound produces a particular action, test if those derived of such a compound have a similar effect. Krebs began then to experiment with derivatives of ornithine and with similar substances to this [8], [10]. However, none of these substances has a similar effect. With the help of new apparatuses, Krebs could determine that the nitrogen in the produced urea was comparable in quantity with the nitrogen in the consumed ammonia. Krebs concluded that the ammonia, and not the amino acids, was the source of the nitrogen. Then, he tried to clar ify the mechanism of the ornithine effect. Krebs realized that the reaction of the arginine, already well known, could be related with the ornithine effect. From quantitative data, Krebs concluded that the ornithine could only be a catalyst, so he inferred that the ornithine with the ammonia produces the arginine, which in turn produces urea and ornithine. Later experiments indicated him that citrulline was an intermediary substance between the ornithine and the arginine. This way the cycle of the ornithine was completed. The discovery consisted on figuring out which mechanism this reaction had. For 20 years biochemistries tried to solved this problem. Krebs made this achievement in nine months.

Computer Simulations
KEKADA is a computational simulation, developed by Kulkarni and Simon, of Krebss discovery of the cycle of the ornithine. Here we will center our description more in the strategies and heuristics than in aspects like computational implementation. When we ask for the representation used by this simulation, we can propose different answers. In a level that we could call of implementation, the KEKADA makes use of a production system, with if-then rules. KEKADA has 64 heuristic, some of which are related with general knowledge and others to most specific knowledge. This way, KEKADAs heuristics rules tries to simulate Krebss strategies and knowledge [10]. One way of seeing the heuristic of this program is dividing them, following to what Kulkarni and Simon call representation of data and representation of expectations. From a general perspective, KEKADAs heuristics could be divided in: a) Processes: generally the chemical reactions and their different elements; b) Substances: here it is not only included information on the substances but also on
"normal" physiology [4] p.6. However, it continued being difficult the observation or at least the indication of the intermediate processes in the metabolism. Otto Warburg had developed a method that allowed conserving tissues in such a way that similar results to perfusions method could be obtained but with a better observational capacity. This technique depended on the possibility of cutting the tissues "slices" between certain limit: around 0.2 mm in ordinary air and 0.5 mm in pure oxygen [8] p. 163.

their respective properties and chemical formulas; c) Experiments: the attributes considered in an experiment are the input data, conditions, place, initial quantities and references about what is measured when it is carried out an experiment. d) Hypothesis: usually a hypothesis is processs description. In a more general level, an experiments representation includes the specification of the objective, dependent and independent variables, instrument or method and measures units. In particular, heuristics associated to experiments are divided in turn in those that propose experiments and those that establish expectations for this experiments. Among the first ones there are 8 heuristic which are of the type: if you are studying a phenomenon with A as reactant and there is a hypothesis that says that A yield C, with B as an intermedi ate product, then carry out experiments in A and in B and compare the rates of formation of C starting from A and starting from B (rule EP2) [10] p. 155. The remaining heuristics of this group are quite similar. The crucial point for Kulkarni and Simon is KEKADAs behavior when some expectations that have been associated to a hypothesis are not corroborated. Here, heuristic of surprise is activated, because there is an unexpected result that violates previous expectations. It is similar to the actual Krebss behavior when he had made experiments with ornithine and unexpected quantities of urea were produced. Grahoff and May have questioned KEKADA, proposing another computer simulation: CDP. The system CDP [5] has more general goals that KEKADA. The CDP has been proposed as a system to discover causal relationships by means of experimental strategies. The CDPs experiment representation is similar to the one that appears in the KEKADA. But it has some important differences. CDP use qualitative rules- as Mills rule of difference - to infer the relevance of causal factors in the experiments [5] p.48. Also, an anomalous result became an expansion of problem space toward an alternative explanation. In this last sense a successful result is reached when they are not anomalies without explanation. This strategy is quite similar to the KEKADAs heuristic of surprise. But, it is in the aspects of design of experiments where some of the most evident differences appear between the CDP and KEKADA. To be able to arrive to the same result that Krebs, KEKADA needs user's intervention. This point is specially criticized by Grahoff and May since the central issues of the discovery would be involved in the decisions taken by the user. Among these decisions, there is the decision of using ornithine for the experiments. Kulkarni and Simon dont find any data about this topic in [7] . The experiments were taken ahead, in this time, for an assistant of Krebs: Kurt Henseleit. In November of 1931, Henseleit carries out a routine experiment in connection with the formation of urea starting from ornithine [8] p. 283. The result, like we saw above, was the production of an unexpected quantity of urea. But, as long as there was not previous evidence to show a relationship between ornithine and the formation of urea, it is not an easy task to suggest a reason why Krebs proposed this experiment .
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5 Some years later Holmes [8] investigates this problem and he doesn't find any decisive element. 6 This decision is made even more difficult of understanding if we consider that the price of the gram of ornithine was of 6 Swiss francs -in Hoffmann-LaRoche Company-. That is: ten

But this is not the only users decisions in KEKADA The others decisions are: a) to study the hypothesis that the origin of the group NH2 in the urea is the ammonia; b) to study the reaction related to the ornithine; c) to choose the possibility that the or nithine was a catalyst [5]p. 50. Grahoff and May criticize the general choice taken by Kulkarni and Simon of not proposing hypothesis about Krebss decisions that don't appear clearly specified in Holmess historical reconstruction. For this reason Grahoff and May don't agree with none of the users decisions. However, we believe that if KEKADA is a historical reconstruction then not proposing hypothesis when the historical data are not clear, it seems a good general strategy. But, although this can be true in general and for the decisions a) and b) before mentioned, it doesn't seem to be good for the decision c). Lets take a closer look at this issue. Immediately after the discovery of the ornithine effect, KEKADA presents several hypotheses, among which there is one that suggests that the ornithine is a catalyst. These hypotheses are generated by the heuristic HG4: if a reaction produces some output, create hypothesis asserting which reactant donates which group to the output substance and that a reactant may be a catalyst [10] p. 156. The proposal of this hypothesis at this point of the simulation come into contradiction with the general strategy suggested by Holmes [7], [8] and accepted by Kulkarni and Simon. This strategy proposes that once it arrives to a result that the previous expectations violates, like it happened with the ornithine effect, it should be determined first the scope of this effect and later the mechanism. Proposing ornithine as a catalyst is, clearly, to invert this strategy. Simon defends himself saying that Krebs seemed to have considered the possibility that ornithine was a catalyst from the very beginning. However, there are several elements against this defense. In first place, Kulkarni and Simon, as we said, consider the strategy of determine first the scope and then the mechanism of a reac tion as a correct strategy. In second place, to consider the hypothesis of ornithine as a catalyst required of the previous rejection of the hypothesis that the ornithine is the source of ureas nitrogen. And in third place the corroboration, of historical character, that this last rejection was neither easy nor quick. However, from the point of view of the experimental strategies, there is a heuristic that have not been considered for computers simulations. Before presenting this point, and the second part of this paper, I will propose to use the notion of problem space as a place from which carry out an exchange between the proposals of the history of the science and cognitive sciences.

A Place for an Exchange: Problem Space

There is a general form of representing a problem inside the field of cognitive sci ences and the classic artificial intelligence. A problem in this research tradition is
times the cost of substances like alanine. And at this time Krebs had run out of funds. The answer of Kulkarni and Simon is, following [7], that Krebs used this substance because it was available.

characterized by the specification of nodes or problem states and operators that allows moving across that space. This initial characterization received an important transformation when in the middle of the 1970 Simon and Lea proposed that the search in certain problems was carried out in a space of instances and a space of rules [16]. This work inspired the idea that its application in the scientific context could be the search in a hypothesis space and an experiments space [10]. Thagard, in turn, has proposed that sometimes the scientists look for in an instruments space [17]. If this multiplication of spaces was to point out to relevant environments of the sci entific activity, it could be evaluated as an interesting contribution. But, starting from the characterization of problems spaces it can be carried out a more articulated proposal. If a problem space is characterized by the way in which the data and the opera tors are represented, then each one of these spaces, if they are really relevant, should respond to a particular and specific characterization. If this is true, then it could be expected that these notions of spaces can help to organize what we have been discussing concerning the discovery of Krebs. But, the utility of these spaces can be bigger than only organize what we have been discussing. In particular these spaces could function as a place from where to emphasize strategies heuristics- and to investigate an exchange between history of scientific practices and computer simulations cognitive science-. To explore this last possibility we will see some studies that have been carried out in cognitive sciences. Kevin Dunbar has investigated the way in which the scientists design experiments in the area of the biological sciences. These studies suggest some interesting points for our problem. Dunbar has proposed a methodology that he has called in vivo approach [3]. This approach consists on registering -in video and audio - the weekly meetings of a laboratory with the purpose of achieving a clearer vision of the way in which the scientists formulate theories, analyze the data and design experiments [1]. This methodology tries to avoid the limits of the protocols that only reveal the reasoning through interviews post-facto [2]. This perspective, according to Dunbar, would also have the advantage of investigating in a previous stage of scientific research. Generally, there is a strategys selection made by scientists and captured by their notebooks, but the in vivo approach tries to go back. This methodology is called by Dunbar a window to the mind of the scientists. This last reference needs an explanation. While Simon's purpose was to investigate problem solving in mind using protocols-, Dunbar, leaves open the possibility that problem solving could be a form of cooperative knowledge. This characteristic is call by Dunbar distributed reasoning. Most of the advantage of the weekly discussion meetings would be rest on the possibility of generating new ideas [1]. In this sense many of the processes that result in successful outcomes can be attributed more to the interaction of the investigation group than to the individuals.

Characterizing a Problem Space for Krebss Discovery

As we said above, there is a key heuristic that none of computer reconstruction have considered. The incorporation of this heuristics seems to be not only historically appropriate but methodologically useful. The determination of the ornithines role is, in our opinion, only a case of a more general problem: the determination of a substance as an "intermediary". The suspicion that the ornithine is a catalyst comes mainly from failure encountered in hypothesis corroboration. This particular hypothesis is to consider ornithine as an intermediary substance. This result is not explained by Kulkarni and Simon - for that reason it is a users election -. But if we consider that there was a heuristic involved in this step, then we must reconsider this users election. We have now to characterize this particular heuristic. Between 1900 and 1910 Edward Buchner and Alfred Wohl proposed different mechanisms for the intermediate metabolism [8], [4]. None of the proposed mechanisms had a widespread acceptance, but in the course of its research, they arrived to some general approaches for testing theories. Those approaches became norms. The most important in these "norms" was the one that proposed how to test an intermedi ary. Buchner had suggested that the lactic acid was an intermediary in the alcoholic fermentation because sometimes appeared in and another disappear of the means in which was carried out the fermentation [8]. Arthur Slator questioned these statements. An intermediary should waste away as quick as he is formed, otherwise this could be accumulated. The example in the fermentation was the glucose. This rule was accepted in the following years. Their power, in the words of the same Holmes [8], was heuristic. This rule was considerer as an axiom, as long as hasnt been questioned. But it was a practical axiom, because always conserved its approximate character . In this sense, this rule about the "intermediary", works like a pragmatic guide. In this way, that rule restricts theoretical possibilities. We suggest that Krebs used this approach, modeling on empirical grounds, as an experimental guide. When Krebs failed using this rule, then he began to suspect a particular role for ornithine in this reaction . If our reconstruction is accurate, then it can be seen as an example on the way in which we could start to configure a problem space in this particular case. But how could we use this problem space as a place for an exchange? In order to do this, we have to develop this case in another direction. In the six months of their stance in Freiberg, Krebs made some experiments that can be seen, from our current perspective, as routinely and without importance [8] p. 271. Those experiments only corroborate what has been already achieved by others. However, among these "routinely" experiments, there is one that had already been conceived by the middle of the XIX century: the synthesis of the urea. The difference
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7 Here we can see an interesting influence of Simon's work in Holmess opinion. In the article of Holmes from 1980 there are not references to "heuristic", but after KEKADAs reconstruction, Holmes began to use conceptual categories like this. [7], [8]. 8 Following this course of reasoning, we could describe Krebss behavior as a representational change. In brief, a representational change is made by a subject when he explores a space problem in an exhaustive way at least in pragmatic terms- and he doesnt find a solution [11].

in this case was that it had been achieved using the technique of cutting the tissue in slices. This experiment opened him the doors for great part of its later investigation. Returning to the main argument, we can say now that the determination that the ornithine was a catalyst responds, in principle, to the 'frustration' in the determination of its mechanism. And here it is where we return to the first point. The possibility to apply the heuristic that we have suggested for the determination of an intermediary was tied mainly to the precision that allowed the method of cutting in slices. But the strategy taken ahead by Krebs can tell us more. To help understanding this last issue, let us return to the studies carried out by Dunbar. Frequently, it is mentioned chance as an aspect of scientific discovery. Serendipity is the name that sometimes received a result that is finding "by chance" or in an unexpected way. The scientists, according to Dunbar, use strategies to favor 'unexpected' results. The scientists "take advantage of these events"; this is: far from being an obstacle, it seems to be something that the scientists look for. In this way, for example, fifty percent of Dunbars experimental results are reported as 'unexpected.' The fact that this result is so common is important. It is not the case that the scientists take any unexpected result and carry out a discovery. Rather, the scientists should evaluate which results are due to methodological error or to any other cause. If the result is unexpected, the first explanation is usually methodological replication, protocol change or the use of a new protocol -. In those cases, an analogical reasoning is used, proposing, for example, similar experiments. The kind of analogy used here is of local type: comparison with experiments or very similar organisms. If the unexpected result is persistent - if there is a 'series' of unexpected results - then the reasoning changes. In this last case new and more general models, hypothesis or theoretical explanations are proposed. Also, there are, among the scientists strategies that Dunbar describes, one that is very important: standard controls. These are controls that have been previously used, validated and standardized. These controls are important to made comparisons. It is a way of achieving confidence and a way to anticipate er ror. Taking in consideration Dunbars studies, we could now rebuild the "surprise heuristic proposed by Simon. The strategy taken ahead by Krebs was indeed centered in the result of the ornithine effect. As we see, the scientists would use what Dunbar calls "controls of knowledge standardized" as a means to anticipate error. With this concept it is pointed out to the knowledge that scientists have about instruments and to the habitual tests to carry out more specific confirmations [3]. And exactly this type of strategies is the one that, in our opinion, would explain the behavior of Krebs. As we saw, the first months of the investigation of Krebs were already dedicated to the routine repetition of experiments carried out by others. To some extent, this could be understood by Krebss necessity of establishing the dependability of the "micro manometer" and of the technique of cutting the tissue in slices for the field of the intermediate metabolism. This way, the strategy of Krebs can be understood as a "control of standardized" knowledge. Here it is important to underline that without these controls it would be difficult to explain the deep impact of the experiment that yield the ornithine effect. Krebs trusted so much in the correct operation of micro manometer that the anomalous result was taken immediately as something important.

This last suggestion is an example of new ways to read history of scientific practices from cognitive science research. But, this inquiry could go deeper. The importance that Krebs gave to the ornithine effect could be explained, to some extent, as we just said, by its anticipation to error. But, Krebss behavior could also be explained by another general strategy. As the historians have point out, Krebs didn't have an important knowledge about how the mechanism of the intermediate metabolism should be neither of the best available theories. In that time there were theories about the operation of the intermediate metabolism [8] that could seduce a more trained scientist. But Krebs didn't have the enough knowledge to see the elegance of those theories [8]. Therefore Krebss search can be described as blind. Curiously, in one of the many alternative Simons descriptions of KEKADA, it is depicted as a breadth-first and, after the discovery of the ornithine effect, like "depth-first [10]. A search of the first kind is usually useful when one doesn't have too much relevant information about the place - inside the "tree" where the solution is. On the other hand a search restricted to one of the "branches" of the tree is usually useful when there is some positive indication that the solution is in some node below of that branch. This positive indication is the ornithine effect. This strategy could be a good explanation about why Krebs chose ornithine. The search should be the most exhaustive one if we had few theoretical and empirical indications about the solution of this riddle. Such a barely guided search could be very receptive to any anomalous result. This can be seen as a strategy, modeling from a historical perspective that could enrich the hypothesis space that we have proposed.

Final Words
We have criticized Krebss discovery reconstructions and suggest some improvements. In particular, we proposed a heuristic for explain certain Krebss historical decisions. This reconstruction could be regarded, in some degree, as a better simulation of Krebss behavior. But, although there are several attempt of simulate human problem solving, this task is almost always done in one way. In this paper we try to rebuild this issue. We presented the sources of creativity as a two faces problem: history of scientific practices and cognitive science -computers and psychology- . From this point of view, our proposal could be seen as an example of a way in which computers simulations can learn from history of science. However, we suggest also that we can read history of science from artificial simulations and cognitive science. We think that this second way is not well explore, although it is sometimes unnoticed used. To reach this goal we proposed the traditional concept of problem space used as a place from which made an exchange between scientific practices and cognitive science. In order to characterize this space we proposed some strategies that could explain key steps of Krebss discovery. This general approach could improve the relationship between computer simulation and history of science. Until now, history of science was viewed only as a source of

heuristics for automatic discovery, but this perspective could be used to see cognitive science as a source of insight and clues to read history of science. In this sense, we could think the interplay between our readings of history of scientific practices and computer simulations as a two-way road. Acknowledgment I would like to thank FONCYT for a research grant (dir. Victor Rodriguez) that supported the work in the paper as well as Secyt, (National University of Cordoba).

References:
1. Baker, L.M.,; Dunbar, K., 2000, Experimental design heuristics for scientific discovery: The use of baseline and known controls International Journal of Human Computer Studies, 53, 335-349. 2. Dunbar, K., How scientists think: Online creativity and conceptual change in science en Ward, T.; Smith, S.; Vaid, S. (Eds.), (1997). 3. Dunbar, K., The Scientist InVivo: How scientists think and reason in the laboratory. en Magnani, L., Nersessian, N., Thagard, P. (edits), (1999). 4. Fruton, J. S.. Proteins, enzymes, genes: the interplay of chemistry and biology. New Haven, CT, Yale University Press, (1999) 5. Grahoff, G.; May, M., From Historical Case Studies to Systematic Methods of Discovery, Working Notes, AAAI Spring Sympsoium on Systematic Methods of Scientific Discovery , Stanford University, March 27-29. (1995). 6. Garcia, P. El papel de las representaciones en las simulaciones computacionales de experimentos en Minhot, L.; Testa, A. (edits). (2003). 7. Holmes, F., Hans Krebs and the discovery of the ornithine cycle Federation Proceedings, 39, 216-225. (1980) 8. Holmes, F., Hans Krebs: The formation of a Scientific Life 1900-1933, Vol. 1. Oxford University Press, Oxford. (1991) 9. Holmes, F, Hans Krebs: Architect of Intermediary Metabolism 1933-1937 Vol. II Oxford University Press, Oxford. (1993) 10. Kulkarni, D.; Simon, H.A. The processes of scientific discovery: The strategy of experimentation Cognitive Science, 12, 139-175. (1988) 11. Korf, R. E. "Towards a Model for Representation Change" Artificial Intelligence 14: 41-78. (1980). 12. Magnani, L., Nersessian, N., Thagard, P, Model-based reasoning in scientific discovery, Kluwer, New York. (1999). 13. Minhot, L. Testa, A. Representacion en Ciencia y Arte, Cordoba, Edit. Brujas, (2003). 14. Roberts, R. Serendipity: Accidental Discoveries in Science., New York: Wiley, (1989). 15. Simon, H, Models of Thought. Vol. I, Yale University Press, New Haven. (1979). 16. Simon, H.; Lea, G. Problem Solving and Rule Induction, en Simon, H. (1979). 17. Thagard, P. Computational Philosophy of Science, MIT Press/Bradford Books, Cambridge. (1988) 18. Ward, T.; Smith, S.; Vaid, S. (Eds.), Conceptual structures and processes: Emergence, discovery and Change, APA Press, Washington DC. (1997).