From Friedrich Wöhler’s Urine to Eduard Buchner’s Alcohol

The physicochemical approach is not at all new in Western thinking. At the very beginning of Greek philosophy, we find Thales’ notion that one substance, water, is the substratum of nature. In contrast to such analytical ideas, we find the idea of a vital principle such as Aristotle’s entelechy. Thus the sharp division... between those who stressed the uniqueness of living matter and those who believed the body to be a mechanical engine (Leicester, 1974, p. 111) has a venerable tradition. It is possible that nonvitalist iatrochemical ideas could be formulated in the seventeenth century with somewhat greater ease than we might at first expect since they could be fitted into a framework of still prevalent alchemical attitudes. In later centuries, however, we see the development of a new attitude. There was no pervasive pattern of authority for the physicochemical view of living processes to fall back on; in order to be accepted, this view depended on the generalizing potential of irreducible and stubborn facts (William James, quoted by A. N. Whitehead, 1925) rather than on a pre-existing framework of assumed but unproven ideas.

It is often assumed that the postulate of a vital force stood in the way of an experimental approach to the study of vital processes: destruction of life, it might be held, entailed destruction of living events, which therefore were not amenable to experimental investigation. Historical facts do not, however, bear out such a simple cause and effect relation between ideas and experiments: the vital force was a gray eminence or convenient refuge that imposed limits on the scope of observation, but it did not stifle experimentation beyond those limits. Thus it would be truer to reverse the postulate: the difficulty in getting certain experimental results were consistent with, or suggested the existence of a vital force. As an example, Leopold Gmelin in the Handbook of Theoretical Chemistry (1829), referring to plants and animals stated that what he called Chemical Physiology investigates the chemical changes which occur in these bodies in so far as [solange] they are under the control [Botmäßigkeit] of the vital force (quoted by Mani, 1956). Some thirty-odd years later, as we saw above (p. 81), Claude Bernard (1857) after his epochal isolation of glycogen from dog liver, strongly contrasted the basis of the entirely vital formation and of the entirely chemical breakdown of glycogen in the liver.

Jennifer Trusted (1996, p. 149) goes further. In a discussion of 19th century vitalism she states that

appeal to vital forces was not intended to end further inquiry but to stimulate it; it was intended to encourage laboratory experiments designed to discover their mode of action. In this respect 19th-century vitalism, though couched in the language of the nature-philosophers (Coleman, 1977, p. 150), was very different from theirs... The later, 19th-century biologists and chemists saw experimental investigation as the basis for inquiry; they did not think the riddles of existence could be solved by thought (Nordenskiöld, 1928, p. 370).

Generalizations do not necessarily apply to all fields. It is likely that in our area attitudes did inhibit discovery. Vitalist attitudes existed here, as elsewhere, as a movable curtain of mystery that receded with new knowledge. Physico-chemical convictions would undoubtedly have hastened the search for cell-free fermentation. Thus Pasteur, driven by Berthelot’s insistence that fermentation is a chemical process that does not need the living yeast cell, did look for fermentative activity in yeast extracts, and used his failure to support his vitalist convictions. Without Liebig’s and Berzelius’s unwillingness to accept yeast as alive, progress in the field would almost certainly have proceeded faster. On the other hand, failure in preparing active yeast extracts was not dictated by vitalist dogma but by experimental difficulties. Thus in the course of the 19th century, ideas promulgated without compelling evidence by some, such as Moritz Traube, remained little more than curiosities, and observations on soluble or so-called unformed ferments were regarded as insignificant exceptions to general rules. Only a compelling experiment could resolve the impasse. It is agreed (Kohler, 1971; Fruton, 1972) that the field of yeast fermentation lay quiescent for 20 years — starting with the end of the Pasteur–Liebig dispute (Liebig had died in 1873) — and was reawakened not by theory but by experiment, Buchner’s experiment. This simple historical fact is a telling tribute to the persuasive power of observation over attitude. Buchner’s accidental discovery of cell-free fermentation was not suggested by the presence or the lack of vitalist assumptions; it was simply an experimental result that dictated its consequences upon believers, and that required further experiments to help convert the unbelievers. As we saw above, Buchner himself found it hard to believe his own observations, because he, as so many others, were under the powerful sway of Pasteur’s ideas. There is a slight possibility — although this may not be fair to Buchner as chemist — that in this case, as one of many, a residual vitalist abdication to rational inquiry was behind a certain lack of probing chemical questions. [Old ideas die hard. In the sixth (!) enlarged and revised English edition (1960) of Fritz Feigl’s standard treatise Spot Tests in Organic Analysis, zymase is included (p. 633) in a list of Individual Compounds for which an identifying test is given.] On the other hand one might argue just as convincingly that lack of progress here was simply the result of the impossibility of predicting the right experiments. Here a good scientific nose or intuition carries far more weight than any philosophical convictions. It is fascinating to read Arthur Harden’s lucid description of his and William Young’s painstaking step by step work that led to the discovery of the role of phosphate and of co-zymase, a co-ferment or co-enzyme, in alcoholic fermentation (Harden, 1932, pp. 42–75).

The impressive ability of chemistry to answer biological questions is often admired and often dismissed by the term reduction or reductionist. It must be emphasized that a fine line should be drawn between reductionist validity and existential identity. Reductionist attitudes fluctuate between two extremes: a belief on the one hand that the complex is, in fact, identical to the simple (in our case, that life is chemistry), and a belief on the other hand that for experimental purposes the complex has to be explained in terms of the simple (in our case, life in terms of chemistry). The former would say that reductionist validity is tantamount to existential identity, while the latter would only agree that reductionism is useful as an experimental device, that its application is derived from and limited to pragmatic validity. Reductionism in its extreme or existential form must necessarily dismiss the part as a representation of the whole, and here, therefore an entity that is not part of the whole takes the place of the whole. On the other hand, reductionism as a pragmatic device can very readily arrange aspects of the whole in a hierarchical order of perceived importance. Most would agree that the pragmatic validity of any selected aspect goes beyond descriptive or experimental convenience, that it in fact permits us to interpret and view the whole as a manifestation of the selected part: the part magnifies the whole and helps to reveal it as a new set of relationships; selection and analysis, are, perhaps paradoxically, a precondition for the discoveries of relationships that enrich the understanding of the whole. In terms of language, one tends to apply the term reductionist to theoretical, and the term analytical to practical concerns. A superb early example of the pragmatic validity of a chemical investigation of the cell is found in a short lecture The Chemical Organization of the Cell by Franz Hofmeister, in which he states that chemical analysis of different tissue constituents has provided a plethora of important findings, and that it turned out to have been a bit premature to assume that the destruction of the living cell completely destroys its vital functions. He stresses that it is only by such destruction that it was found possible to establish the presence in cell of agents, such as enzymes, that are active during life. This lecture, rewarding reading to this day, is an elegant vindication of the value of the analytical approach to the unraveling of vital processes, (Hofmeister, 1901). (For an appreciation of Hofmeister’s work, see Fruton, 1992, Ch. 5.) Reductionism has often been rejected on first principles because of the predictive limitations of going from lower or simpler to higher or more complex, a problem that is enshrined by the word emergence and that has pretty much disappeared as a viable object of enquiry. The fascination with reductionism does not go away. A recent symposium The Limits of Reductionism in Biology (1997) has received probing reviews (Williams, 1997; Bray, 1997), aspects of which smack of at least a partial return to vitalist attitudes. The present writer has not yet seen this book, and so an independent evaluation is not possible, but the readers of the present volume will undoubtedly be delighted to know that the ancient debate on methods and conclusions in biology is far from over.

In the case of biology the immense and pervasive success of chemical approaches toward understanding, toward prediction and toward medical success has achieved, and continues to achieve, pragmatic validity. None of the various possible degrees of reductionism addresses itself to the ultimate meaning of reductionist validity, and it is in this search for significance (in our case, a search to answer the question as to the strength of chemistry to answer biological questions) that differences in attitude come to the fore. To cite a specific example, Fleming (1964) has made the important point that the decision by the physiologists du Bois-Reymond, Brücke, von Helmholtz and Ludwig to substitute physicochemical forces for vitalist ones was intended as a program for research rather than the enunciation of a Weltanschauung... Mechanism was coextensive with scientific knowledge, but not with the range of legitimate curiosity. More than a hundred years later one can see a fascinating reversal: in the research laboratory one may on occasion find it useful to reject purely physicochemical approaches to one’s experiments or questions, but it does not follow that one has to adopt a corresponding philosophical approach to nature. For example, K. F. Schaffner (1967) states:

Given the current state of biological science, there may be good heuristic reasons for not attempting in all possible areas to develop physicochemical explanations of biological phenomena, and good reasons for attempting to formulate specifically biological theories. This, however, is an argument which supports an irreducibility thesis for methodological reasons. Any attempt to twist this into a claim of real irreducibility for all time is, in the light of recent work in molecular biology, logically untenable, empirically unwarranted, and heuristically useless.

The question of the relation between chemistry and biology is exactly analogous to the question in physics as to the relation between mathematics and the physical universe: Why does chemistry work?, why does mathematics work? Biology is unavoidably chemical, just as physics is unavoidably mathematical. It is fatuous to ask whether one could have predicted a priori that chemistry would be so immensely fruitful for an understanding and study of biology, and mathematics similarly essential for an understanding of physics. It should be clear that opposition to a chemical approach for the study of living phenomena, inherent in some vitalist attitudes and found in some modern analogies to vitalism, is tantamount to denying that mathematics is an essential prerequisite to an understanding of the physical universe. Physics evolved through a period when deductions based on mathematical analysis were rejected since they were incompatible with dogma, and biology will undoubtedly weather similar attacks, born of ignorance or prejudice, on the understanding of biological phenomena.

There is no doubt that the advances in enzymology in the last decade or so of the 19th century contributed massively toward a swaying of scientific attitudes away from vitalist approaches. However, the results obtained by enzymological and other studies did not suffice to limit the vagaries of biological thinking. Thus it was the embryologist-turned-philosopher Hans Driesch who at the beginning of the 20th century powerfully resuscitated vitalist ideas (Driesch, 1908) based, characteristically, on his own — and as it turns out, erroneously interpreted — important research results (see Fleming, 1964, pp. xxv-xxvi). In 1911 Jacques Loeb gave a celebrated address whose object was to discuss the question whether our present knowledge gives us any hope that ultimately life, i.e. the sum of all life phenomena, can be unequivocally explained in physicochemical terms (Loeb, 1912). These words, although advanced as a question, are strongly reminiscent of the 1847 School of physiologists and of Berthelot’s words in 1860. There is, however, a fundamental distinction: while earlier workers’ views were dictated by faith based on induction, the latter’s deductions more than fifty years later were fashioned by conviction based on further evidence.

Ernest Nagel stated in his classic book The Structure of Science (1961):

Vitalism of the substantive type advocated by Driesch and other biologists during the preceding century and the earlier decades of the present one is now almost entirely a dead issue in the philosophy of biology. The issue has ceased to be focal, perhaps less as a consequence of the methodological and philosophical criticisms to which vitalism has been subjected, than because of the sterility of vitalism as a guide in biological research.

An earlier version of topics treated in this book was published (Nagel, 1950–1951) in which elegant and clear arguments are presented for the rejection of the organismic approach, which to a large extent has replaced the vitalist approach as an alternative to physicochemical theories of living processes.

One cannot of course pin down a certain instant when a given idea formally disappears from the stage of accepted opinion. C. H. Waddington has described the process well: around the time of my student days the whole controversy vanished (Waddington, 1961). However, even later the vitalist attitude had not disappeared completely. We can cite two interesting examples. Richard Willstätter, Nobel Laureate in chemistry, prominent opponent of the idea that enzymes are proteins and of the use of column chromatography as an analytical method, stated in his very last paper (Willstätter and Rohdewald, 1940)

It must be concluded that Buchner’s press juice and macerated yeast react with sugar in a fashion which differs from that of living yeast.

He elaborated on this in his celebrated autobiography, published posthumously:

Some fermentation potential can be isolated [from yeast], but I consider it different from the fermentation effect of the living yeast cell.

WILLSTÄTTER (1949, p. 63, English translation 1965, p. 66)

Willstätter’s views were not unique. Thus in 1940, again, F. F. Nord, who was to be the distinguished editor for thirty years (1941–1971) of the annual Advances in Enzymology stated in a detailed review on the mechanism of alcoholic fermentation:

It is not conclusive if, from the enzymatic behavior of structurally destroyed systems... forceful conclusions as to the qualitative actions of the parent systems within the living cell are drawn.

NORD (1940)