P96-205Structures of a Scientific/Technological Revolution

Veröffentlichungsreihe der Arbeitsgruppe Public Health Wissenschaftszentrum Berlin für Sozialforschung

ISSN-0935-8137

P96-205

Structures of a Scientific/Technological Revolution

Coincidence, Order and Creation

of Latitude for Action in the Evolution of an Innovation:

Penicillin and Antibiotics von

Janos W olf

Berlin, August 1996

Publications series of the research unit Public Health Policy Wissenschaftszentrum Berlin für Sozialforschung

D -10785 Berlin, Reichpietschufer 50 Tel.: 030/25491-577

Structures of a Scientific/Technological Revolution

Coincidence, Order and Creation of Latitude for Action in the Evolution of an Innovation:

Penicillin and Antibiotics *)

Abstract

The subject of this investigation is a frequently observed phenomenon in scientific development: the dis­

continuity between a discovery and a revolution; a discovery that is seemingly unappreciated and forgotten but later, in connection with a revolutionary development, appears even to be its point of departure, thereby acquiring great respect. Taking the emergence of penicillin, FLEMING’S discovery (1928/29) and the ensuing revolutionary development of the antibiotics sector in the early forties as an example, the hypothesis is devel­

oped that the discontinuity can be viewed as a generally occurring, structural pattern of scientific genesis. A macrostructure of scientific development gives rise to discrete research sequences, which lead to leeway for revolutionary restructuring; and, namely, to the extent they potentially complement each other - though invisi­

ble to the actors involved. Chronologically staggered, similar “premature” developments/inventions of a cyclic latitude have no visible links from the microstructural perspective but only later in macrostructural retrospect in which the cyclic links become partially visible. Thus, there is a general barrier not only to concrete progno­

ses, growth and simulation models but also to the evaluation of scientific results. So-called “premature” or also “parallel” multipie discoveries/inventions of a similar nature are genuine constituent elements in the order of a cyclic scope of action (latitude/leeway).

Such a macrostructural latitude produces various possibilities of a more or less accidental microstructural triggering of a revolution, which possibilities represent discontinuities and create in their entirety the latent po­

tential of a maturing revolution. The revolution is triggered by an event (discovery/invention) to the extent the latter is able to stimulate or activate the latent potential of different social actions for a new structuring. If the restructuring is triggered by an event in the scope of action, all the latent possibilities of triggering the revolu­

tion appear in retrospect as spatiotemporal discrepancies in the co-evolution of the macrostructure and micro­

structure, as discontinuities. These discontinuities are, on the other hand, continuities in the macrostructure, where they occur as organic patterns of development between discrete research sequences.

The cyclic scopes of development tend toward events with a threshold-value function that usher in struc­

tural upheavals. Its scientific/technical conspicuousness and social effect, or the conspicuousness with which it brings about the restructuring of a scope for action, and in which it therefore represents the seed for the morphology of the revolution, depend on the magnitude of a closing cyclic scope of action or event with a threshold-value function. The magnitude of an event can be defined as the potential for direct links with future events in the network of action or direct links in retrospect (magnitude in a given present). Since this magni­

tude is open from a future-oriented point of view, it can never be precisely defined; and therefore, to no greater extent, the significance of an event. In terms of an infinite yardstick of development, a cycle with a small magni­

tude can, for instance, lead to a minirevolution in the scientific laboratory, and a cycle with a large magnitude to a revolutionary social upheaval.

The positing of an “internal/external” set of problems is inappropriate in respect to the macrostructure of the scopes for action, whereas that of an enfolding and unfolding movement of innovative/dissipative and so­

cially conservative structures with no breaks in its evolution is more plausible.

One possibility of describing the process from a theoretical standpoint is presented with the help of a sto­

chastic network method. The macrostructural happenings are interpreted as supersubjective, spontaneous self-organization of act structuring.

Regardless of whether individuals or program groups are involved, the subjects and their acts in the super- subjective structuring of acts do not simply appear as the free “designers of their reality” but as persons in­

visibly “driven” by social history within the scope of action of a cyclically active supersubject (totality of ac­

tors segregated in terms of space and time), under the aegis of which they are granted degrees of freedom to shape matters themselves within a certain amount of individual leeway as actors.

This “driven nature” must therefore not be understood in the sense of automatism but as the dominance of an emerging order of action over the latitudes of the individual acts contained therein, the interlinkage of which produces the act-related order.

*) This article is the greatly abridged version of a study titled “Structures in the Origin and Development of a Scienlific/Technolo- gical Revolution - How did the accidental discovery of penicillin bring about the radical change from a diffuse order of social acts to the complex order involving the medical/technological antibiotics revolution?, dissertation (German), Free University of Berlin, 1996, P. 232.

- 1 -

Contents

Introduction 3

1. A scientific revolution in the portrayal of publication rates 5

2. Discontinuity as a microstructural phenomenon in scientific

development 7

2.1 An accidental event

7

How was penicillin discovered?

2.2 A discrete research sequence arises

8

Why did FLEMING discontinue his research into penicillin?

2.3 Feedback between discrete research sequences

9

Why was there once again recourse to the work FLEMING did in 1929?

2.4 Feedback and selection

10

Why did work begin anew on penicillin?

2.5 The cell of a new research structure arises

10

How did the “Oxford Group” arise?

3. Discontinuity as a macrostructural phenomenon in scientific

development 11

3.1 Formation of structures and origin of latitude for the revolution

14

3.1.1 How did chemotherapy arise from structural chemistry, dye-related chemistry,

bacteriology and pathology?

14

3.1.2 How did antibiotics research result from biology, mycology, bacteriology and how did it

become part of chemotherapy?

14

4. Discontinuity as a pattern of the co-evolution of microstructur and macrostructures during the rise of the scientific/technical revolution 15

5. The origin of a sequence of actions with a threshold-value

function in the co-evolution of the microstructure and macrostructure

How did the decisive experiments involving penicillin become the threshold to a new development of science, technology and the social sector ?

17

6. Revolutionary structural upheaval - the sudden change from a diffuse to a complex structure

How did a revolutionary social cycle of acts develop in the fields of science, technology,

ecnomics, the social sphere and politics in the USA?

18

- 2 -

7. Discontinuity as a structural phenomenon of sociopolitical differences

How did the specific national conditions determine the international spread of the

revolution?

23

7.1 Great Britain

23

7.2 Australia

23

7.3 Soviet Union

24

7.4 Germany

24

7.5 Japan

25

8. Attempt to provide a theoretical framework for the dynamics of the

action structure 26

8.1 The act/event structure as a network

26

How can the historical process be represented as a network?

8.1.1 The GERT network method

26

8.2 FLEMING’S research sequence in the GERT network

27

8.3 The inchoate penicillin research program in the GERT network

29

9. Basic features of the hypothetical structural model 33

9.1 The relationship between discovery and revolution

33

Provisional characteristics

9.2 Structuring of various totalities

34

9.3 Divergence and convergence - differentiation and integration

34

9.4 Time and perception

35

9.5 Internal time and external time

36

9.6 Cycles and quanta of acts as special units of effect

36

9.7 Formation of latitude

37

9.8 Accident and order

38

9.9 Implicit and explicit order in the network

39

9.10 System and network flow theory

44

9.11 Self-organization

47

Appendix

50

Literatur

53

- 3 -

Introduction

Over and over again, it seems, grand discoveries are temporarily forgotten only to surprisingly take center stage in a process sometime later; this we call a

scientific re­

volution.

Among the numerous discoveries accorded a comparable fate, the discovery of

penicillin

by FLEMING in 1928/29 is one of the most striking ones. Not simply because of the incredible constellation of events in which the discovery occurred but more be­

cause of its sensational emergence in the limelight of scientific and public attention more than ten years later - namely because of another event, the discoveries made by the FLOREY group in 1940/1941.

Three years earlier - in 1937 - the then president of the USA, ROOSEVELT, had commissioned a committee of the

National Academy of Sciences

to prepare an ap­

praisal of future developments in the sciences and their impact on society for the next 75 years. This committee was formed with competent and recognized scientists of the time. Good predictions characteristically succeed for directions in which work is al­

ready being done. But the omission of the most impressive

new

developments o f the coming decades was striking, e.g. nuclear energy, for which the fundamental work of HAHN and MEITNER followed one year later. Jet aircraft, rockets, the utilization of space, radar, the development of electronic computers, the transistor, quantum elec­

tronics and many other scientific and technical developments were not mentioned. Nor could the committee foresee the revolutionary changes in medical therapy occasioned by penicillin and antibiotics as well as the major industry resulting therefrom in just the next few years, although FLEMING’S discovery was already eight years old and the ex­

perimental work that was to set a scientific revolution rolling began one year later - in 1938. (TOWNES, 1983).

And FLEMING? He admitted that just at the moment when certain changes in his bacteria culture became visible he did not have the slightest suspicion that this could be the beginning o f something extraordinary. What are the causes of such phenomena?

Are they regrettable exceptions, the consequence of unfortunate misunderstandings, or are they more likely the rule in scientific activities marked by a large number of subjec­

tivities^) - specialist knowledge, competition, vanities, ties to special interests, a re­

bellious attitude toward ideas and results when they are not in harmony with one’s own views.

For many people those are grounds to assume it is also possible to establish the rea­

sons for the discontinuous development of science by analyzing the behavior of scien­

tists and their social entanglements.

There is a long tradition in the writing of history. An attempt is made to render the genesis of the “factual” comprehensible from the sequence in which it is generated; a generation which, it would appear in retrospect, is enriched with experiences related to the past. Since KUHN’s critique of historiography at the latest, many representatives from fields involving the psychology and sociology of science tend to view this proce­

dure more as a falsified depiction of real processes to the extent that what happened is described as being interconnected in a way different from what the actors experienced at the time (KUHN, 1962, 1967).

No matter how one tries to shed more light on the interrelationships; the central question on which efforts seem to unify is elucidation of singular discontinuities in sei-

- 4 -

entific development. The problem is posed perhaps most markedly in the question: are there discoveries before their time? (STENT, 1972)

In the case of the efforts hitherto examined in order to find an answer to this ques­

tion, an unsatisfactory remainder seemed to me to have remained open in as much as an attempt is made to explain the phenomenon by an analysis of the internal events in a

“scientific community”: the paradigmatic problem-relatedness and/or specific scientific viewpoints and their transformation within the same. But what is odd is why the evo­

lutionary relationship of what is separate, i.e. the various paradigmatic fields of work, has not been made the subject of investigations to equal extent, and why the same at­

tention has not been paid as well to the constellation of relatively autonomous and separate events in science as well as to the movement of this constellation, although many well-known cases of discontinuity in scientific development provide signs there­

of. Is it not possible that the paradigmatically bound processes are only substructures in a structural configuration arising in the evolutionary course of a division of work?

If this possibility exists, it cannot be without consequences for our understanding of science.

This question has given rise to the intention to find an answer by analyzing a con­

crete case of scientific development.

The aim was to find out whether a discontinuity in scientific development is also caused by a structural background of discreet actions and what position it holds in the evolutionary dynamics of science, in the birth of a revolution.

A special area of scientific was chosen for the analysis: the rise of the antibiotics sector.

The result I arrived can be presented, to begin with, in lapidary form as a provisional hypothesis. It reads:

It was not the discovery of penicillin by FLEMING in 1928 - as often assumed - that was the starting point for the rise of the scientific sector of antibiotics but the mode of a decades-long, self-structuring and, at this time, invisible realm of discoveries/inventions consisting of discrete sequences (fields) of research that tend to complement each other and thus converge. The revolutionary emergence of the antibiotics sector has arisen from the co-evolution of a macrostructural and microstructural development of science. A spatiotemporal lati­

tude for various constellations permitting the revolutionary event to be triggered arose as the macrostructure;

a coincidence-related constellation leading to its true triggering as the microstructure. The discontinuity be­

tween FLEMING’S discovery and the revolutionary development of the field more than ten years later proves to be a repeatedly occurring pattern involving a sequential macrostructure in which FLEMING’S discovery is one of the sequences, one that is referred back to and is gradually favored in a process of selection. The macro­

structure is dominant for the occurrence of the revolution in as much as it creates a latitude for diffuse, dis­

crete research sequences that provide the initial potential for the shape of the revolution. In this indirect way it was possible for FLEMING’S astounding accidental discovery to bring about a microstructural revolution that specifically modified and activated the latitude of discrete research sequences for the initiation of the revolu­

tion.

In contrast to the research-based method another path has been chosen in the follow­

ing to depict the situation; this is done with the intention of making it easier for the reader to follow the ideas. Headings have been chosen for the individual chapters that always emphasize that structural aspect inherent in the historic events.

Questions involving a simple picture that renders the scientific revolution visible are the starting point and we now want to look at them.

Each of the answers to these questions will initially stand on its own and only yield a isolated picture so that the insight into the analyzed process formulated with the objec­

tive cannot be reached until the end of the remarks - in their interconnectedness.

- 5 -

1. A scientific revolution in the portrayal of publication rates

Figure 1 shows how the publication rate developed as a function o f time. The two functions to be seen result from counting the relevant publications listed in the German bibliography of journal articles comprising series A and B under the entry of

penicillin

and/or

antibiotics.

Series A contains the articles of German-language journals and se­

ries B the articles published in international journals.

We shall begin with a simple look at the illustration. As the investigation proceeds, more and more new aspects will - as I assume - become amenable to perception so that by the end of my remarks it will be possible to see the picture that appears as an expression of a complex process.

expression "Antibiotics" without "Penicillin"

Figure 1: Number of publications as a function of time

Figure 2: Coefficient of generation of new directions:

relation of number of the publications on the subconcepts of "Penicillin" / "Antibiotics"

to the number of publications on the generic notions (cf. Figure 3)

Figure 3: Generation of successive discoveries from Penicillin (based on ROLINSON, 1979)

-1 -

The function is started with the famous discovery of penicillin by Alexander FLEMING in the year 1928, a discovery he published in 1929, Its fame is not based, how­

ever, on an immediately forming group of followers but on developments that began in the early forties. It was only the rapid rise of a new group of scientists with their work on penicillin and other antibiotics that made the hitherto little known FLEMING an in­

ternationally respected scientist and, finally, a Nobel prize winner more than ten years after his discovery. FLEMING’S publication was cited only three times in the years after his discovery between 1929 and 1940.

2. Discontinuity as a microstructural phenomenon inscientific development

2.1 An accidental event

How was penicillin discovered?

“ it takes luck to discover and the mind to invent.

and neither can do without the other”

GOETHE 1817

FLEMING’S discovery has several dimensions of accidentally:

Dimension (1) - the discovery is accidental in respect to a latitude for sequential scientific development of the macrostructure.

Dimension (2) - the discovery is accidental in respect to another sequence of scientific developments in biol­

ogy where for decades mycologists had been dealing with the effect of fungus (including Penicillium) on mi­

crobes, whereas FLEMING, an immunologist and bacteriologist, had no expert knowledge of fungi.

Dimension (3) - the discovery is accidental in respect to a constellation of nature-, life- and work-related cir­

cumstances.

(The first two dimensions will not become apparent until later in the paper, the third dimension will be gone into in this section.)

In 1928 Alexander FLEMING was experimenting with pathogenic staphylococci. He grew them in dishes by the customary method and checked the cultures at certain in­

tervals. One day one of his dishes, on which colonies of

Staphylococcus aureus

were growing, displayed contamination by a colony of molds. An incident that had to be reckoned with once in a while because the lid was raised for the purpose of controlled ventilation. But this time FLEMING noticed a strikingly prominent, bacteria-free circle caused by the colony of mold. The

staphylococci

had apparently been decomposed in this surrounding area. The phenomenon he observed involving the lysis of the

staphy­

lococci

impressed FLEMING so much that he subjected the mold to closer examination.

His momentous observation fell on a quite normal working day; yet it had taken place only because of an incredible constellation of circumstances. The accidental dis­

covery had come about due to the coincidence of a large number of different events unrelated to each other:

- FLEMING’S absence, which was just long enough because he had to write a chapter for a book, led to the time span required for the growth stage of the staphylococcus culture and mold.

- The lectures of a Dutch physician that led to the appointment of a mycologist whose work was directly subordinate to that of FLEMING’S.

- The mycologist’s luck in isolating a potent penicillin-producing strain of the mold.

- An inappropriate laboratory that contaminated the atmosphere with spores.

- The high probability that FLEMING either forgot to incubate his culture dish or in­

tentionally refrained from doing so.

- The fact that FLEMING’S laboratory was specially sensitive to outdoor temperatures.

- The fact that the requisite temperature was caused by a cold wave at a time of the year that would normally have been unsuitable for the discovery.

- The visit by his colleague PRICE, who induced FLEMING to take another look at a dish he had already checked and put away.

- The circumstance that the dish had escaped destruction because of the completely inappropriate methods for the handling of used culture dishes.

All these events came together in FLEMING’S laboratory in a way that could not be completely reproduced today.

If

one

link in the chain had been missing, the discovery would not have been made!

This complex of interrelated events explains the rarity of the observation in view of the fact that the contamination of bacteria cultures by molds were an everyday occur­

rence in laboratories.

2.2 A discrete research sequence arises

Why did FLEMING discontinue his research into penicillin?

Three main reasons made FLEMING discontinue his research into penicillin:

(1) Neither he nor other scientists in his entourage succeeded in isolating or extracting the effective substance.

(2) In his research program FLEMING did not pursue a strategy involving possible chemotherapeutic applica­

tion of penicillin due to his basic immunological approach and the corresponding research climate under the direction of WRIGHT.

(3) The decisive reason was, however, the following: it seemed utterly impossible to make more of the volatile preparation than had already been achieved; the difficulties, vagaries and risks that threatened to take up many years of valuable research time, perhaps without any notable result, made it appear sensible to discontinue the work.

FLEMING cultivated his original strain in bouillon and found out that a strain of fun­

gus was growing in the surface culture and excreting the effective substance into the nutrient medium after grayish-green coloration due to sporulation.

FLEMING’S first methodical practical efforts to demonstrate the antibiotic effect of the unknown substance can be traced back to the decisive observations o f the object he made in accidental conditions.

He imitated, namely, the diffusion processes. The result was exciting: apart from

Coli

bacteria and PFEIFFER’s

influenza bacilli

all the pathogenic organisms proved to be susceptible to different degrees, inter alia

staphylococci, pneumococci

and

diphthe­

ria bacilli.

That proved that an antibiotic substance was involved. FLEMING called it

penicillin.

For all his medical life FLEMING had been interested in the antibacterial effect of blood and antiseptics; that is why he emphasized that

penicillin in vitro,

in a solution of 1 in 600, completely inhibited the growth of the staphylococci but did not disturb the leukocyte function to any greater degree than a common nutrient solution.

By relating the effect of the

penicillin

to the

phagocytosis

and by relating his experi­

ments almost exclusively to antibacterial investigations

in vitro

he was determinedly addressing scientists of his own paradigmatic orientation. In retrospect one might ask what the one or other reason was for the fact that FLEMING and the scientists around him did not work more stubbornly on an elaboration of the discovery, even though

- 9 -

they knew that the penicillin solution, as an

antiseptic,

was drastically different from any other known antiseptics.

There was, however, a simple and thoroughly plausible explanation after all the failed attempts to isolate and extract the

penicillin',

the assumption, namely (and one shared by FLEMING), that it would not pay to take on the difficulties, the unforeseeable hurdles and uncertainties, especially since it was quite questionable whether an eco­

nomically manufacturable preparation could ever be obtained.

2.3 Feedback between discrete research sequences

Why was there once again recourse to the work FLEMING did in 1929?

Microbial antagonism had been researched in scattered fashion by various disciplines for several decades, e.g.

biology, bacteriology, immunology. The way the problem was viewed had progressed so far by the end of the thirties that an integrative, biochemical complex of questions about all the substances found to date was to be found in the genesis and logic of this development. CHAIN was then the first person to pose this integrative question, to deal with it and arrive at a result that formed the foundation for integration, from a new scientific point of view, of the hitherto diffuse research sequences within the scope of microbial antagonism and for acti­

vation of its common potential.

In 1935 Professor H. W. FLOREY was appointed to the chair of pathology at Oxford.

His subject was experimental pathology. He intended to build up a corresponding de­

partment. A certain internal biochemical flanking of his work was required for this pur­

pose. FLOREY himself, however, had no specific biochemical training, which is why he turned to Sir Frederick Gowland HOPKINS, the director of the

Sir William Dunn School o f Biochemistry

in Cambridge, one of the world’s leading centers o f biochemi­

cal research. He was supposed to advise FLOREY on the appointment of a suitable bio­

chemist. The choice fell on Ernst Boris CHAIN, who had emigrated from Germany due to his Jewish descent. One of CHAIN’S main scientific interests was how neurotoxic snake venoms acted. At Cambridge CHAIN had found that some of the most effect snake venoms had the property of inhibiting glycolysis and alcoholic fermentation in certain conditions. CHAIN continued this work at Oxford.

Within the scope of this work, which began in 1936, CHAIN prepared an overview by recording bacteriolytic agents. In so doing, he made the acquaintance of various cases involving the lysis of one bacterial type by another; especially bacteriophages and their powerful bacteriolytic capacity, on which there was already extensive literature at the time.

CHAIN reports: “I thus stumbled, more or less accidentally, across the well-known phenomenon of microbial antagonism, first described very lucidly by Pasteur & Joubert (1877).” (CHAIN, 1971:

296/297)

This circumstance - and not, for instance, any direct knowledge of the significance of FLEMING’S result - led to feedback in the research that impacted a whole realm of sequential fields of science.

CHAIN collected some 200 reports on growth inhibition caused by the effect of

bac­

teria, streptomycetes, fungi

and

yeasts.

He fell back on the results of a research sector that had been compiled by separate fields in the course of decades. There was no doubt that in many cases growth inhibition was caused by specific metabolites produced by the various microorganisms.

- 10-

The salient point that excited CHAIN’S interest was, however, that the chemical or biological nature of the inhibiting substances was nearly unknown. That is why clarifi­

cation thereof appeared to him to be an interesting and worthwhile field o f research.

2.4 Feedback and selection

W hy d id w ork begin anew on penicillin?

The discoveries of FLOREY’S colleagues, especially those of CHAIN, did not arise - as customarily assumed - via direct recourse to FLEMING’S discovery. They arose, rather, (a) from the first inspection of major, spatio- temporally splintered discoveries of various discrete research sequences; (b) from a new biochemical complex of questions posed by CHAIN, which served to unify this sequence and (c) from the gradual selection of obser­

vations considered especially interesting in a three-year work process. FLEMING’S discovery was also one of the observations selected! The linkage of FLEMING’S discovery to the discoveries of CHAIN and FLOREY’S colleagues came about as back-coupling to discrete research sequences, and only one of them was FLEMING’S research sequence.

In 1938, after having dealt with this subject for several years, CHAIN ran across FLEMING’S 1929 publication in the

Journal o f Experimental Pathology.

(FLEMING, 1929)

FLEMING’S reports impressed CHAIN because of the clearly described bacterial an­

tagonism and the open biochemical questions. In the course of difficult experiments CHAIN finally found out that penicillin was not a

protein

but a low-molecular sub­

stance. A method developed at the same time for the freeze-drying and desiccation of blood serum brought the decisive methodological advance in the mastering of penicil­

lin’s chemical instability.

A brown powder that displayed impressive antibacterial activity was yielded. With the exception of the

sulfonamides

no antibacterial preparation that displayed compa­

rable properties was known at the time. It was possible for the first time to demon­

strate the chemotherapeutic effect of penicillin in animal experiments.

2.5 The cell of a new research structure arises

H ow did the “ O xford Group” arise?

Originally, the Oxford group was not founded with the aim of working on the practical utilization of penicillin as a team. The group turned into a “penicillin team” only in connection with successive selection of the penicillin problem within a much broader research program.

Only after the chemotherapeutic effect of the preparation was demonstrated did a number of scientists begin to cooperate on programmatic research into

penicillin.

CHAIN expressly pointed out accounts that falsified the process by imputing there had been an “Oxford team” that had worked from the very beginning - due to correct evaluation of FLEMING’S observation - with the aim of making the preparation useful for practical purposes.

“ The group assembled after, not before, our first chemotherapeutic experiments on mice, for the pur­

pose o f speeding up the w ork, and i t was not so much an organised team as a group o f colleagues w ith different backgrounds o f expertise collaborating w ith each other to achieve obvious objectives in the m inim um o f tim e.” (C H A IN , 1971:301).

The instability of the substance originally made any possible practical utilization ap­

pear very doubtful. That the work began as a contribution to the war effort lacks any basis. But this motive did play a major role later on, namely after the therapeutic effec­

tiveness of

penicillin

for humans had been demonstrated. Chain reports the following about the beginning of the work:

- 11 -1 1

“The only reason which motivated me to start the work on Penicillin was scientific interest. I very much doubt, in fact, whether I would have been allowed to study this problem at that time in one of the so-called mission orientated industrial laboratories. The research on Penicillin which was started as a problem of purely scientific interest, but had consequences of very great practical importance, is a good example of how difficult it is to demarcate sharp limits between pure and applied research.”

(CHAIN, 1971 301)

The first congregation of several researchers to investigate

penicillin

took place in a different situation. Only after results demonstrated the chemotherapeutic effect of

peni­

cillin

in animal studies did FLOREY’s department tend toward a certain concentration on research into the matter. To make progress as fast as possible several colleagues in the department were asked to work together on the pharmacological, bacteriological and chemical aspects of the program. But this group, too, could not really be called a

“team”.

The “Oxford group” was consolidated only now in connection with the research program to be coped with, the development of which involved several stages of purifi­

cation with the aim of risking clinical tests on humans. With the still very impure prepa­

rations there was a risk of humans being infected. (ABRAHAM et. al., 1940).

As Fig. 1 shows, the penicillin revolution becomes visible with the rapid growth of a scientific community and their publications.

The foundations had been created for this at Oxford: In 1940 an article appeared in

The Lancet

on the chemotherapeutic power of

penicillin

in the case of bacterial infec­

tions of mice. There was something dramatic about the results described since they pointed to a substance for whose effect no comparable dimension was hitherto known.

(CHAIN et. al., 1940) One year later this group produced a report, published again in

The Lancet,

that attracted considerably more attention. This time it was reported that the fungus metabolite

penicillin

displayed notable chemotherapeutic effects in the case of clinical bacterial infections. And what was especially impressive, the effect also ex­

tended to infections caused by

Staphylococcus aureus.

Until then there had been no antibacterial substance that displayed a satisfactory chemotherapeutic activity against the same

in vivo -

nor any member of the

sulfonamides,

the only group of highly ef­

fective antibacterial substances known to date.

This work played a key role in the inchoate revolutionary development; it is at the base of the rapid growth in publications on penicillin.

3. Discontinuity as a macrostructural phenomenon in scientific development

The historiographic material made it appear advisable to access that the discoveries by FLEMING and FLOREY’s group from the structure of the roots to be found in their deeper past. My assumption was the fol­

lowing: if it were possible to find divergent and convergent tendencies in this structure, the rapid agglomera­

tion of scientists who came together due to the discoveries of FLOREY’s group, thereby triggering the expo­

nential growth of the publication rate (Fig. 1), would have to stem from a self-forming convergence of divergent research sequences.

Tracing the historiographically ascertainable roots back to the middle of the 19th century proved to be a good idea. The search for further roots of the penicillin - and antibiotics - revolution led to branching paths of scientific development, the formal structure of which can only be delineated with the help of discoveries that are particu­

larly striking in connection with the revolution. These discoveries can be assigned to roughly four long-term formations of research sequences which, starting with their origins, can be interpreted as divergent formations, with each of them displaying for it-

- 12-

self a temporally quantized, precipitous structure. From this point of view, they follow paradigms and discourses that are relatively separate from each other. From the point of view of the revolution, however, they converge in terms of content and carry ele­

ments of the discoveries made by FLEMING and FLOREY’s group as well as features of the revolution in general. In their entirety they form a fragmented, converging, spatio­

temporal configuration with a tendency toward mutual complementation. This differ­

ence is hinted at schematically in Figs. 4, 5, 6. The discoveries contained in these illus­

trations mark four distinguishable formations of research sequences involving the problem of antagonism. One of the formations arose with research into bacterial an­

tagonism in the field of bacteriology following a discovery by PASTEUR in 1877. A sec­

ond formation arose from investigations into antagonism between plant substances and microbes, for example between fungi and microbes in biology. A third formation can be found in investigations into the antagonism of chemically yielded substances (e.g. syn­

thetic dyes) and microbes. Chemotherapy began on that basis at about the turn o f the century. A fourth formation, finally, arose from research into antagonism between mi­

crobes and endogenous substances produced by humans and animals, especially patho­

genic microbes in the field of immunology. The development of penicillin as a research sequence is also to be found in the formation of research sequences containing discov­

eries of relevance to antibiosis; it led to antibiotics research, not, however, as a forma­

tion per se but in its interlinkage with the other formations, and in this interlinkage it turned out to be a formation of chemotherapy and became a subdiscipline thereof.

CHAIN’S complex of integrative biochemical questions led to a visible convergence of research in the fields of biology, bacteriology, chemotherapy, penicillin, other antibiot­

ics and biochemistry on the basis of structural chemistry(!)

• Discovery of antagonism bacteria - bacteria chemicals - bacteria

Figure 4: Apparent succession of discoveries of the antagonism (linear accumulation in retrospection)

1943

preformation 19'28 1940

invention. i--- r ---►

innovation application

Figure 6: Interpretation of the sequential convergence of discoveries on antagonism-phenomenon (interpretation of space-time-arrangement)

- 1 4 -

3.1 Formation of structures and origin of latitude for the revolution

3.1.1 How did chemotherapy arise from structural chemistry, dye-related chemistry, bacteriology and pathology?

When looked at from the viewpoint of the discoveries made by FLOREY’S group the convergent cycle of the past had two divergent origins. The first origin is to be found in structural chemistry, which goes back to KEKULE. From there a divergent sequence of the network leads to the manufacture of synthetic dyes and to the rise of a dyes industry based thereon. In the 19th century this sequence in the network still converged with other divergent sequences, with bacteriology on the one hand and pathology on the other.

With the new possibilities of dying medical preparations and bacteria a certain affin­

ity of dyes for some microbes was detected. This, in turn, was the origin of the devel­

opment of a new, divergent sequence in the network about the turn of the century - with Paul EHRLICH’s program and theory of chemotherapy. Important advances were made in the twenties, and a breakthrough was achieved in the thirties with the fabrica­

tion of sulfonamides. Chemotherapy came about due to the convergence of discoveries and inventions (greater mutual complementation and a corresponding new view) in the divergent development sequences of structural chemistry, bacteriology, dye-related chemistry and pathology.

The second origin of the cycle goes back to the emergence of bacteriology. Its se­

quential development drifts through biology, biochemistry and pathology to antibiotics research.

3.1.2 How did antibiotics research result from biology, mycology, bacteriology and how did it become part of chemotherapy?

Between 1871 and 1928 scientific historiography shows at least eight research sequences in which observa­

tions similar to those of FLEMING’S were made. Between them there is in every case a spatiotemporal “gap”

similar to the one between FLEMING and FLOREY.

After the microscope was invented there were new impulses and possibilities for the observation of microorganisms. It was on this basis that PASTEUR discovered the prin­

ciple of antagonism, initially between anthrax bacilli and another certain type of mi­

crobe. In the ensuing years this phenomenon was sporadically observed ever more fre­

quently and finally called

antibiosis.

Among the observations there were, with spatio­

temporal segregation from each other, a large number of phenomena involving the an­

tibiosis of molds and bacteria (about which, incidentally, FLEMING knew nothing at the time of his discovery).

This was accompanied by the spatiotemporal intervals of all the other relevant dis­

coveries pertaining to the problem of antagonism which represent spatiotemporal pat­

terns of discontinuity in the way paradigmatic fields relate to each other. (Fig. 6 can only hint at this)

- 1 5 -

4. Discontinuity as a pattern of the co-evolution of microstructur and macrostructures during the rise of the scientific/technical revolution

FLEMING’S discovery is not the beginning of the revolution but the final chapter in a spatiotemporal series of converging research sequences largely invisible to the participants, which sequences finally underwent a cul­

minating closure in those of FLOREY’S group.

W hat position did FLEMING’S discovery hold in the macrostructure?

As the last in a long series of comparable observations it was fated to be temporarily forgotten. But luck was still on his side, for he had to wait only ten years to be remem­

bered again, and even to be awarded a Nobel prize. The others had to wait for decades and, of course, no longer learned how their contribution, in a spatiotemporal series of discoveries invisible to them, converged with others and finally shared in a grandiose development. Thus, the “gap” between FLEMING’S discovery and those made by FLOREY’s group is primarily, in macroscopic terms, not a subjective problem o f over­

sight and forgetting but a phenomenon involving the self-structuring of spatiotemporal- ly discrete sequences of activities and their results. Yes, as a “gap” or discontinuity it is, among others, part of the pattern of a spatiotemporal series of converging discover­

ies and discrete research sequences. Not until a certain degree of macrostructural order was reached in science was it possible for an integrative question with a high level of feedback to arise. This question was, in a certain sense, prepared by a decades-long, convergent drifting of various research sequences. But: behind the backs o f those who brought about this order, for they were all pursuing separate aims. The macrostructural order, however, was “searching for” its own goal and one day “drove” one of the per­

sons involved to adopt this goal.

For the appearance of the revolution there was a scope of probability that can be in­

terpreted on the basis of plausibility considerations (cf. Figs. 7,8).

Figure 8: Fictitious representation of an other possible constellation of development in probability-space

- 1 7 -

5. The origin of a sequence of actions with a threshold-value function in the co-evolution of the microstructure and macro structure

How did the decisive experiments involving penicillin become the threshold to a new development of science, technology and the social sector ?

At the time the decisive experiments were performed in FLOREY’s laboratory, the informational (various types of scientific knowledge) and material (technical outfitting, agents, etc.) circumstances comprising the preced­

ing macrostructural latitude were referred back to and integrated as a precondition. In a certain sense they dis­

appeared in the informal and material results of these experiments, or were annulled in a HEGELian sense.

Many

preceding, separate actions, with results strewn across many decades, actions that had evolved or developed in different directions, were now folded into or turned into

one

sequence of actions and events. The latent convergence (invisible potency of mutual complementation) in past, divergent, programmatic research sequences now appears, emerging from its invisibility and forming the threshold to new programs of action.

The field of antibiotics could not only have arisen via various paths of penicillium re­

search but also through the discovery of another highly effective, antibacterial sub­

stance, e.g. the discovery of

streptomycin.

Accordingly, the rise of antibiotics research as a revolutionary event did not neces­

sarily depend on FLEMING’S discovery of penicillin. A cogent reason for this assump­

tion is the fact that antibiotics emerged from several different research sequences. Each of them could have triggered the visible rise of a new research structure with an out­

come that would have been comparable to the integrative effect of the results obtained by the FLOREY group. Fortune let events develop along the lines of FLEMING’S discov­

ery and gave the macrostructural order a corresponding mode.

Characteristic of this macrostructural order is a statement by CHAIN, whose funda­

mental work on the biochemistry of penicillin created the initial foundations for con­

centrated penicillin research:

“I believe that the field of microbial antagonism had become ripe for study when we started our own investigations in 1938. The existence of antibacterial substances produced by micro-organisms had been well documented with many examples, and it was of obvious interest to study their biological and biochemical properties. We would have started our research programme on these substances even if Fleming’s paper had not been published, and if we had not done so, someone else in some other labo­

ratory in the world would have taken the initiative.” (CHAIN, 1971: 302)

Ever greater occupation with antibacterial substances followed the macrostructural genesis of research into the problem of microbial antagonism -initially independent of FLEMING’S emergence. Within this latitude there was a wide variety of microstructural constellations all drifting in the direction of a revolutionary development. Without FLEMING’S discovery the threshold value for the outbreak of the revolution would have been reached by another path, and a new integrative viewpoint would have arisen. As regards the macrostructural constellation, the discovery of another bacterial antibiotic would, in fact, have been more probable than FLEMING’S discovery.

When a closer look is taken at the situation, it can be seen that the work done by WAKSMAN had a long-term and systematic structure. It was only a matter of time be­

fore

streptomycin

would emerge from his research sequence. A combination of the questions posed by CHAIN and the findings expected in regard to

streptomycin

was more probable than the combination with FLEMING’S unimaginably accidental discov­

ery. Not only that, a look at the probability of the research constellation makes the possibility of the opposite development appear much more plausible. Without

- 18-

FLEMING’s discovery bacterial antibiotics would have appeared first because of the systematic work being done in the field; the scope for action in the field of microbial antagonism would have been activated from this direction.

And due to the long occupation with bactericidal substances in biology one would also have stumbled across molds, worked through them systematically and thus arrived in such a way at the prehistory of penicillin and then at penicillin itself via program­

matic research. The bacterial antibiotics would have had a catalytic effect on penicillin research - and thus there would only have been a certain reversal o f the events within the intrinsically rather stable scope for action.

With FLEMING’S accidental discovery there was, however, a more improbable devel­

opment, at least when the overall constellation of convergent drifting by the various re­

search formations is looked at. This unusual coincidence was required for the devel­

opment’s realm of probability to be given a correspondingly different mode.

The functions shown in Fig. 7 would then have been in reverse order due to the op­

posite genesis of the process. The antibiotics function would be shifted to a later date due to the lack of additional stimulus by penicillin, and the penicillin function would follow at some interval or another, (cf. Fig. 8) The fact that the story took an opposite course is due to an accident on which, however, the revolution did not depend from the macroscopic point of view. For its appearance there was a realm of probability whose temporal and spatial dimension may not be sharply definable but which - regard­

less thereof - is conceivable in a thought experiment on the basis of logical plausibility considerations. (See hatched areas in Figures 7 and 8). It is just as impossible to define the vertex of this probability realm in terms of time as it is to define the totality of de­

velopment possibilities of sequential scientific actions stemming from the co-evolutive interaction of the microstructural and macrostructural configuration. The discontinui­

ties are, to a certain extent, the structural interstices (network dilutions) in the se­

quence of actions. They are bridged by a wide variety of feedback loops so that the ac- tion/event structure is thus stabilized in the course of change.

6. Revolutionary structural upheaval - the sudden change from a diffuse to a complex structure

How did a revolutionary social cycle of acts develop in the fields of science, technology, economics, the social sphere and politics in the USA?

The entire wealth of diffuse scientific knowledge and technical experience that flowed into the decisive experi­

ments with the social application thereof and was thus folded into the results was now pressing for integrative inclusion in a complex program of science, technology, economics, social policies and politics.

What used to be the precondition for discovery and invention in terms o f social re­

sources for diffuse scientific programs is today, in integrated programs, the purpose­

setting condition for the unfolding and/or development of technology, production and social utilization. From this point of view, none of the social areas is ever autonomous or operationally closed. The penicillin program during the Second World W ar was - similar to the program to develop the atomic bomb - treated as a “secret weapon”. Se­

cret agreements between the USA and England were the foundation for an information barrier that locked the rest of the world out from sharing in the scientific and techno­

logical advances achieved, especially the enemies in the war.

For at just about the same time as FLOREY - uncertain about what the near future would bring - departed for the USA (June 26, 1941), the country’s president, ROOS- VELT, signed executive order No. 8807, establishing the Office of Scientific Research

- 19-

and Development” (O.S.R.D.). This office was assigned the task of doing research on scientific and medical problems of relevance to the national defense. Dr. Vannevar BUSH

was appointed its director. President R O O SEVELT and D r. BUSH brought together a se­

lect group of people from forty-two scientific and consultative committees and coun­

cils. Together with the National Research Council they formed the O.S.R.D. Committee on Medical Research (C.M .R .). The chairman of the C.M .R. was D r. A . Newton R IC H ­ ARDS. The committee was supposed to balance the medical profession’s research in­

terests with the pragmatic needs of the military.

Programs were only confirmed by the committee if it was possible to prove that the results to be expected would help improve the Allies’ military position. The most diffi­

cult decision the commission had to make soon pertained to penicillin.

The individual stages of convergence between political, scientific and industrial ac­

tions were inaugurated with the arrival of FLOREY and H E A T L E Y in the USA.

On August 7 he visited A .N . RICHARDS, professor of pharmacology at the University of Pennsylvania, in whose laboratory FLO R E Y had once worked for a few months fif­

teen years earlier. These old ties were now of special value, since RICHARDS had shortly before been appointed Chairman of the newly formed Committee on Medical research (C.M .R.), a department of the Office o f Scientific Research and Development

(O.S.R.D.). The latter had been created by order of the President on June 28, 1941 in order to stimulate and encourage scientific research on medical problems affecting the nation’s defense. (RICHARDS, 1964: 442). The C.M .R. decided early on to transfer pro­

duction of natural penicillin to commercial companies; the more speculative research into the structure and possible chemical synthesis of penicillin, however, was placed under the strict control of the O.S.R.D. Synthesis programs were supposed to be kept as separate as possible from the fermentation programs, although that necessitated higher cost estimates. RIC H AR DS and BUSH proceeded on the simple assumption that the commercially interested companies would not develop penicillin from the fundamental questions yet to be clarified.

Despite all the restrictions, there was a wide-spread conviction that the Germans and Japanese would develop the penicillin industry. This assumption was seen to be justi­

fied by the preconditions those countries met: Germany’s beer production and the Ja­

panese Sake industry; they were based on highly developed fermentation methods. In addition, both countries attached great importance to technological progress. M oreo­

ver, the Germans had acquired many years of experience in organic chemistry and the chemical industry.

And everyone still had easy access to the initial publications on penicillin. Given free scientific intercourse and the absence of the special situation entailed by the war, most of the reasons given would surely have sufficed to bring about relative, continuous in­

ternational progress in the penicillin program in line with national resources. The ob­

structions caused by the war situation, however, additionally amplified the discontinu­

ous progress that would otherwise only have been specifically modified by national preconditions.

The treatment of war casualties with penicillin began on April 1, 1943. On July 16, 1943 the Office of Pharmaceuticals and Cosmetics ordered the agency for war produc­

tion to equitably allocate the entire industrial yield of penicillin to the army, navy, pub­

lic health service and the O.S.R.D. (C.M.R.) in keeping with their needs. From June to December 1943 penicillin production was increased by more than 5000% over the period from January to May 1943. By the end of April 1944 it was possible to satisfy the de­

mand of the army and navy. (cf. Figs. 9,10,11)

N u m b e r of P o u n d s *

1200000 1000000

800000 600000

400000 200000

1200000

Year

All others Erythromycin Chloramphenicol Tetracycline Oxytetracycline Chlortetracycline Dihydrostreptomycin Streptomycin

Penicillin A n t i b i o t i c

Penicillin has been m e a s u re d in international units of potency (Louis S. G o o d m a n a n d Alfred Gilman, The Pharmacological B a s is of Therapeutics, N e w York: Macmillan Co., 1956, p. 1239)

Figure 9: Output of leading antibiotics: 1948 and 1956

Figure 10: Percent to total output of leading antibiotics: 1948 and 1956

Science

1940 1942 1944 1946 1948 1950 Time (Years)

Social - Network

(Scientific, clinical, industrial, military, political)

1940 1942 1944 1946 1948 1950 Time (Years)

Industry

1940 1942 1944 1946 1948 1950 Time (Years)

Economics

Figure 11: Correlative development at the beginning of the Penicillin-revolution

-2 3 -

7. Discontinuity as a structural phenomenon of sociopolitical differences

How did the specific national conditions determine the international spread of the revolution?

The extreme situation of the war made the specific national relationships of social and scientific development stand out to a special degree, for the exacerbated situation caused by the war strengthened the ties between science and society. But these ties became visible only years later after the archives were gradually opened.

The differentiated shape of the medical revolution is seen to be a variable that depends on national, scientific, technological/industrial, economic, social, military and political conditions.

7.1 Great Britain

While FLOREY and HEATLEY were sojourning in the USA the laboratory production of penicillin was also continued at Oxford.

Between 1944 and 1945 “penicillin” is said to have attained the status of a house­

hold word in the country of its birth. (HOBBY, 1985: 125). Initially, however, the British pharmaceuticals industry registered penicillin in the course of the year between the first report from Oxford in

The Lancet

on August 24, 1940 and the second on August 16,

1941.

The tense situation of British industry entailed by the requirements of war produc­

tion had convinced FLOREY, however, that faster progress - if at all possible - was more likely to be achieved in the USA.

Initially - as long as the penicillin program was still encumbered by immense uncer­

tainties - the war had a more inhibiting than stimulating effect on the research project.

A leader on penicillin that appeared in

The Times

on August 27, 1942 called the at­

tention of the British public to FLEMING’S discovery. After intense preparations for re­

search and production had been made as a result of FLOREY’s trip to the USA the British side had to fear that it would be left behind in the exploitation of a discovery made in their country. But the dispute that set off was not only a symptom produced by the safeguarding of national interests but also one evoked by increasingly manifest personal conflicts arising from individual shares in the development of penicillin and the possible candidacy for a Nobel prize, which was awarded to FLEMING, FLOREY and CHAIN in 1945.

7.2 Australia

The Australian history of penicillin begins in October 1943. Major Percival BA7.ELEY was sitting in an armored vehicle in northern New Guinea when news reached him from headquarters in Melbourne. There were no instructions about a war-related op­

eration; instead, he was to go to the United States at once and look into the possibili­

ties of penicillin production.

In May 1944 Winston CHURCHILL convened an Imperial Conference in London. The Australian Prime Minister, John CURTIN, was also represented. He had apparently heard about FLOREY and penicillin from General BLAMEY, the Australian Commander in Chief. (BICKEL, 1972: 223). Thereupon CURTIN asked FLOREY whether he could not visit Australia in this matter. FLOREY did not require any special persuasion; he most likely considered it his honorable duty to do his home country this service now that he enjoyed public respect.