Introduction to Biologics, A History of Agents Made From Living Organisms in the Twentieth Century

7/27/2019 Introduction to Biologics, A History of Agents Made From Living Organisms in the Twentieth Century

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BIOLOGICS: AN INTRODUCTION

Alexander von Schwerin, Heiko Stof and Bettina Wahrig

Over the past century, our bodies have increasingly become exposed to the phar-maceutical action o incorporated biological substances. Some o these havebecome so ubiquitous that we have even stopped thinking about them as bio-logics. We swallow our daily vitamin pills; we rely on vaccines and antibiotics

when microbes prolierate; we account or the adverse efects o cortisone; welive a more-or-less normal lie thanks to regular injections o insulin or an organtransplant; and we place our aith in monoclonal antibodies when a tumour hasbeen diagnosed. One recent textbook denition o biologics provides us withstill more examples:

By denition biologics are proteins and/or derivatives thereo that modulate theimmune system, downregulate the inammatory response or support tumor specicdeence. Biologics also known as biologicals or recombinant therapeutics donot represent one homogeneous group o drugs. Monoclonal antibodies, usion

proteins (along with other proteins, toxins and radionucleotides) and recombinantproteins, growth actors, anti- and pro-angiogenic actors, and expression vectorsgenerating proteins in situ may all be included as members o this class o pharma-ceuticals.1

Tis recent denition does not include vitamins, hormones, antibiotics or vac-cines, although they have been and sometimes still are categorized as biologicsor biologicals.

Te term biologics rst emerged in connection with national health-carelegislation and the control o vaccine production in the US more than a hun-dred years ago. For a long time, there existed no equivalent expression in Europe,

where terms like Naturstofe, Wirkstofe (biologische Arzneimittel) or mdica-ments biologiques were common. Tese terms encompassed a broader range osubstances like hormones, vitamins, enzymes, as well as plant extracts, especiallyi they worked in ways comparable to animal enzymes. Tus, all o these termshad diferent meanings and connotations, while sharing a common reerence tonatural products in one way or another. Teir introduction into pharmaceuticalterminology opened up a semantic eld that prolierated wildly and exuberantly


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2 Biologics, A History o Agents Made From Living Organisms in the wentieth Century

both in the US and in Europe throughout the twentieth century. In the rst halo that century, the adjective biological was oen used to indicate a lie reorm-ist or naturalist understanding o the human body. Biological agents, whichin spite o their small quantity had such intense efects, became prototypes orideas o naturalness and purity. Tis characterization o biological enzymes, tox-ins, antitoxins, etc. resonated with broader eforts and rhetorical strategies toredene the boundaries between nature and technology: in chemistry or exam-

ple, the new technique o catalysis was ennobled by the act that nature seemedto have invented it. However, this benecial nature turned into a threat whencatalysis involved microbial contaminants.

Te aim o this volume is not to provide another denition o biologics, butto introduce the concept o biologics as a ruitul perspective or the historyo pharmaceuticals, medicine and science. Te act that in many Western coun-tries a great number o very heterogeneous substances were subsumed under asmall number o terms, all o which captured their biological origins, demon-strates the importance o industrially produced biological scientic objects and

pharmaceuticals in the twentieth century. Hence, the notion o biologics is lessa problem o natural versus articial ontology, than o socio-technical order.2Biologics have posed specic scientic, industrial, medical and legal problemsand are hence o particular interest to any deeper understanding o the so-calledtherapeutic revolution, its scientic bases and its relationship to the standardi-zation o medicinal drugs, the dynamics o regulation and risk-management

policies, the industrialization o precarious substances, the economics andpolitics o natural things and the development o biotechnology since the latenineteenth century.3

Since biologics are both o natural origin and produced using advancedindustrial methods, the historical study o biologics provides a useul research

perspective, enabling new insights into the genealogy o industrial and consumermedicine and o the lie sciences. It also contributes to the historicization o the

production o naturalness, alongside the corresponding processes o representa-tion and intervention.4 Te very practical context, in which terms like biologicsemerge, already indicates that biologics transgress the conceptual (and material)boundaries between the inanimate and the living, between the organism as a

whole and its organic and inorganic contents, as well as between nature and its

technical modication. Accordingly, this volume highlights diferent, but inter-dependent aspects o biologics: the production and regulation o substancesmade rom living organisms and the signication o biological remedies as both

powerul drugs and agents o naturalness. In light o the todays rapid develop-ment o new biological entities such as recombinant DNA-derived products,biomolecules and biosimilars, this book ofers historical perspectives that stretchar back rom our age o biotechnologically processed substances and that illu-


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Introduction 3

minate the changing relations between laboratories, clinical services, industrialsettings and regulatory bodies.

In this introduction, we will provide an outline o the historical study obiologics. A suitable approach to the topic is to examine the emergence and evo-lution o the terms biologics and biologicals and so the rst three sections

will concentrate on the ate o these and related concepts in both the US andEurope. Historical examination o discourses on biologics reveals this groupo substances to be a distinct historical object that becomes tangible as a resulto diferent contingent processes in the medical, technological, economic andsocial history o the twentieth century.

In the last three sections o this introduction we will urther explain this perspec-tive by introducing the main categories used to characterize biologics as historicalsubjects. Tose categories reect the larger subdivisions o the present volume andoutline a comprehensive historiographical perspective on biologics. While therehave been many studies on blood, vaccines, hormones, vitamins or avonoids, ouraim is to relate these substances to discourses and practices such as standardization,naturalization, politicization, industrialization and regulation. It is thereore neces-sary to begin with an outline o the regulatory and cultural concept o biologics andto use this term as an analytical tool or acquiring new perspectives on the history o

pharmacology, health-care legislation and biomedicine.Te authors o this volume deal with the production, regulation and con-

trol o biologics and include gendered, colonial and consumer perspectives. Te

contributions originated rom a workshop held at the echnical University Braun-schweig in Germany during the oggy days o March 2010. Te workshop was oneo a series unded by the European Science Foundations network DRUGS.5 Itrepresented the rst attempt to bring together the histories o diferent substancesand materials, such as vaccines and sera, plant extracts, genetically engineered pro-teins, cells, tissues and organs. Given the complexity o these substances, we hopethat the contributions to this volume will encourage readers to take a comparative

perspective on the history o biologics in the twentieth century.

Standardizing Biologics in the US in the First Halo the wentieth Century

Te term biologics rst emerged in the United States in the early twentieth cen-tury. It was inextricably connected with governmental eforts to standardize andcontrol therapeutic, prophylactic and diagnostic agents like sera, viruses, vac-cines and antitoxins. Although it is di cult to establish exactly when these terms

were introduced, it is clear that ederal statutes and regulations played a crucialrole in bringing a range o diferent substances together within the conceptualramework o biologics and biological products.6


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In some respects, the history o biologics begins with the diphtheria anti-toxin. By 1895, laws regulating biological products had been enacted by thegovernments o France, Germany, Italy and Russia. In the United States, many

people were concerned about the saety o vaccines, given that they were injectedand could have rapid and adverse efects i contaminated. Nevertheless, these

products were initially rushed to market and their use proceeded without regu-latory saeguards.7 But the reluctance to regulate these new substances changedin 1901, when thirteen children died aer being treated with a diphtheria anti-toxin made rom the blood o a tetanus-inected milk-wagon horse named Jim.8Soon thereaer, a similar tragedy in Camden, New Jersey resulted in deaths andinjuries that were attributed to a tainted biological product. In 1902, the execu-tive body o the National Convention or Revising the Pharmacopoeia decidedto include Serum Antidiphtherium, the most important serum product o thetime, in the Pharmacopoeia o the United States because o the increasing use oit and other serum products.9

Tat same year, discussions about the risks o vaccination also resulted inmore stringent government regulations. Under an Act o Congress in 1902, all

viruses, sera and toxins sold in the United States were required to conorm toestablished standards. Tis law marked the beginning o a regime or licensing obiologics and vaccines that, according to Carpenter, ultimately evolved into theFood and Drug Administration (FDA), which today is responsible or the con-trol o biologics in the US.10 Indeed, when the FDA celebrated the seventy-h

anniversary o the Food and Drugs Act o 1920, it also celebrated the BiologicsControl Act o 1902, thus implicitly suggesting a continuity in the regulationo biological products.11 However, in the original law o 1 July 1902 there wasno mention o biologics, biologicals or biological products.12 Instead, it waso cially designated as An Act to Regulate the Sale o Viruses, Serums, ox-ins and Analogous Products in the District o Columbia, to Regulate Interstatera c in Said Articles, and or Other Purposes.13 Te laws scope was denedto include any virus, therapeutic serum, toxin, antitoxin, or analogous productapplicable to the prevention and cure o diseases o man.14 Obviously, the advento biologics as a new category o therapeutic substances was steeped in the his-tory and science o immunization.15 Te laws main targets were vaccines, but itsreerence to analogous products began paving the way to include other biologi-

cal products.16

With this new legislative ramework in place, subsequent years witnessed theemergence o various labels to describe these products. Te rst documented useo biologics occurred in 1912 when the pharmacological editor o the Calior-nia State Journal o Medicine, Fred Lackenbach, used the term in an overviewto describe a variety o diferent substances. Unlike other contemporary drugs,the use o these substances would demand accurate clinical and bacteriologi-cal diagnosis and a thorough knowledge o the indication, dosage and mode o


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Introduction 5

administration.17 o the benet o pharmacists and physicians, this implied thatbiologics were products ill-suited to the huge market or sel-medication beingserved by department stores and mail-order houses.

Lackenbach considered the year 1902 to have been crucial in the ormationo this new class o pharmaceutical products. For that year saw not only the Actto Regulate the Sale o Viruses, Serums, oxins, but also a second, related actapproved on 1 July that sought to reorganize the US Public Health and MarineHospital Service (later designated simply as the Public Health Service or PHS)and entrusted its Hygienic Laboratory with the task o perorming all neces-sary tests and inspections.18 ogether, both acts established the legal rameworkor ederal regulation o biological products designed or human use and estab-lished the authority o ederal institutions to regulate biological products andensure their saety or the American public.19 Subsequently, the PHS went aboutestablishing a regime o vaccine control and it was in this context that severalnew generic terms emerged. Te Annual Report o the Surgeon General o the

PHSin 1908 harked back to the tragedy o 1901 in explaining that all possiblecare should be taken or the exclusion o the tetanus bacillus rom all biologic

products.20 Other authors reerred to biological products or substances o abiologic nature, but all o these terms were used only sporadically.21

It seems that the catchy term biologics emerged only when economic andbusiness interests were at stake. In his overview, Lackenbach used the termbiologics in addressing the commercial pharmacist (i.e. the man who handles

these products or revenue).22

Similarly, the Commercial Interests Section othe Journal o the American Pharmaceutical Association published a summaryentitled the sale o biologicals in which the terms biologicals and biologics

were used synonymously.23 In 1917, the Biological Department o Eli Lilly andCompany published a small treatise on Elements o Biologics designed to pro-

vide the companys representatives with standard knowledge about antitoxinsand vaccines. Te denition used or biologics read: A line o products, includ-ing serums, smallpox and rabies vaccine viruses, bacterial vaccines, antigens, andextracts, toxins, etc., the manuacture o which depends upon the use o bacteriaand bacterial products.24 Lillys instructions suggest that the market or antitox-ins and vaccines was expanding. And indeed, by 1921, some 41 establishments

were licensed to sell no less than 102 diferent sera, toxins and analogous prod-

ucts, posing considerable challenges to ederal regulators.25

Te use o generic terms became more and more common as ederal authori-ties invented new structures to cope with the regulatory challenges in the 1920s.In 1923,Public Health Reports compiled a list o national agencies and organiza-tions associated with the regulation o biologics.26 Around the same time, theRevision Committee o the US Pharmacopoeia established the Sub-Committeeon Biologics.27 Te most important ederal agency was the Hygienic Laboratoryo the PHS, given its responsibility or testing biological products and licensingmanuacturers (see Figure I.1).


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FigureI.1:TeregulationobiologicsseverelytaxedtheresourcesotheHygien

icLaboratoryothe

PublicHealthServiceatBethesda,Maryland,U

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Introduction 7

Under the 1902 Act, all Diphtheria Antitoxins sold in the United States wererequired to conorm to the standard established by the PHS. Tis standard

was based on the Ehrlich Immunity Unit preserved at the Royal Institute orExperimental Terapy in Germany the rst biological standard in the world,

prepared by Paul Ehrlich himsel in 1897.28 During the First World War, thisno longer seemed acceptable and the Hygienic Laboratory began developing itsown biological standards.29 Activities in viruses, serums, toxins, and analogous

products were conducted under the supervision o the laboratorys director andusing personnel drawn rom its our divisions: pathology and bacteriology, zool-ogy, pharmacology and chemistry. Te laboratory was increasingly responsibleor enorcing the law, regulating the sale and routine inspection o businesses, as

well as conducting research (see Figure I.2).30 Ensuring the purity and e cacyo sera and other agents was the specic task o the Division o Pathology andBacteriology. In 1920, these responsibilities were classed under the heading Bio-logics (routine examination).31 And in 1923, all o these activities were broughttogether in a h division responsible or the Control o Biologic Products. 32 In1930, the Hygienic Laboratory was re-named as the National Institute o Health(NIH).33 Finally, in 1937, work on biologics control was granted its own divi-sion within the NIH, the Division o Biologics Control.34

Institutionalizing the control o biologics involved expanding existing regula-tions on vaccines, sera and antitoxins to include arsenical drugs, blood and blood

products. Te scope o the Hygienic Laboratorys activities increased accord-

ingly, especially aer 1917 when the United States entered the First World War.35

Beore the war, the US had depended on Germany or its supply o salvarsan andneosalvarsan, arsenical drugs used in the treatment o syphilis. With the entry othe United States into the war, the Federal rade Commission abrogated German

patent rights and licensed American manuacturers to produce their own arseni-cal drugs: It seemed a logical step to bring the testing and control o arsenicalsunder the same system as biologics, and so the Hygienic Laboratory was given thisresponsibility.36 In 1920, the Surgeon General complained that routine controlso biologic products had come to dominate the work o the Division o Pathologyand Bacteriology with 3,525 biologic products examined in that scal year and that as a result other research problems were being neglected.37 Furthermore,blood products became a main ocus o the Laboratorys research activities. In

1934, the NIH issued the rst licenses to manuacturers or the production oa human blood product, a preparation o protein rom human placental extractthat was designed to immunize against measles.38

Aer the entry o the United States into the Second World War, many othe scientic advances were driven by the need to provide US military personnel

with the best medical care possible, including ready access to sae blood productsand protection against diseases. Troughout this time, the Division o Biolog-


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FigureI.2:By1938,t

hestafattheNa

tionalInstituteoHealthresponsibleorbiologics

controlhadincreasedmarkedly.S

our

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Reproducedcourtesyo

theNationalLibraryoMedicine.


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Introduction 9

ics Control established standards or a number o blood products.39 Korweksuggests that the whole blood or plasma language was added as a result o theuse o blood transusions during the Second World War.40 Obviously, the con-stant redenition o terms was necessitated by developments that modied the

practice and regulatory scope o biologics control. But a number o scandalousincidents also contributed to the ux o terminologies. In the 1930s, over a hun-dred people, among them many children, died aer consuming an improperly

prepared sulanilamide medicine, Elixier Sulanilamide.41 Te manuacturerMassengill & Company had used diethylene glycol as a solvent, resulting in mass

poisoning in 1937 and a huge public outcry. o strengthen consumer protectionin the emerging national ood marketing system, the Pure Food and Drugs Acto 1906 was replaced in 1938 by the Federal Food, Drug and Cosmetic (FD&C)Act, which now dened biological products as drugs. From then on, both the1902 Biologics Control Act and the FD&C Act comprised a dual legal sys-tem responsible or the regulation o biologics.42 Subsequently, when the PublicHealth Service Act was re-codied in 1944, the dual status o biological productsturned out to be the main issue o concern to legislators. According to Section351 o the PHS Act which at the time was oen conusingly reerred to as theBiologics Act , the term biologics now included any

virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or deriv-ative, allergenic product, or analogous product, or arsphenamine or its derivatives (orany other trivalent organic arsenic compound), applicable to the prevention, treat-

ment, or cure o diseases or injuries o man.43

Standardizing Substances made rom Living Organisms in Europe

Te example o the United States illustrates the emergence o biologics at theintersection o government regulation and the economy. Biologics was a regula-tive term introduced to enable state-controlled production o these substancesand it played a major role in the institutionalization o drug control in the US.However, there existed no equivalent term in Europe, although the standardiza-tion and regulation o substances made rom living organisms was common inmost European states rom the late nineteenth century onward. Instead, othergeneric terms emerged rom diferent contexts, rst and oremost the term bio-logische Wirkstofe (biologically active substances). As the European case shows,rather than conning historical analysis solely to the topic o standardization,one must instead consider the institutionalization, regulation, activation andcasual use o these agents, as well as their hybrid status, their semantic elds,their political meanings and socialized actions.


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In the nineteenth century, state vaccination policies be they based onconsent or compulsory were common in many European countries, such asEngland, France, Prussia, Germany, Italy and Russia.44 Laws ostering and regu-lating vaccination had already been enacted by the 1860s and 1870s. In England,it was the responsibility o the General Board o Health in conjunction with theEpidemiological Society to supervise vaccinations mandated by the VaccinationActs rom 1867, 1871 and 1874. In Germany, the smallpox epidemic o 1871had prompted theReichs-Impgesetz (Imperial Vaccination Law) o 1874 which,aer 1876, was implemented by the Imperial Health O ce (Reichsgesundheit-

samt). Te law introduced compulsory vaccination as part o the state welaresystem.45 Te introduction o sera therapy highlights some o the problems char-acteristic o biological substances, the most urgent one being the di culties oensuring their e cacy, i.e. dening their efective dose. Tere was no stable rela-tionship between the absolute quantity o any kind o serum and its efectivenessagainst a specic disease such as diphtheria. Ever since the tuberculin afair o1891, when Robert Kochs cure or tuberculosis spectacularly ailed, serum andantitoxin therapy in Germany had been viewed with suspicion. Regardless otheir therapeutic and economic viability, sera were considered to be precarioussubstances in need o state control and evaluation (Wertbestimmung). Te newimperial law o 1895 regulated the production and distribution o sera, restrict-ing their sale to pharmacies and declaring them prescription drugs. In addition,only state-certied serum was allowed on the market.46

Te situation was diferent in France, where the Pasteur Institute had beengranted a monopoly on the rabies vaccine and was also exempt rom regulationsconcerning diphtheria serum. Under the heading prophylactic and therapeu-tic agents or use against contagious diseases, the French law o 25 April 1895grouped together attenuated viruses, therapeutic sera, modied toxins andanalogous products.47 Te abrication o these biological products requiredgovernmental permission and only authorized institutes could produce and dis-tribute serum in France. Pasteurism resulted in the Public Health Law o 1902.48Unlike Germany, where the saety o the new substances was broadly monitored,the French governments main goal was to exclude inefective serum. And soFrench legislation was limited to dening approved producers and leaving qual-ity control in their hands.49

According to Canguilhem, the bacteriological age, notably the develop-ment o sera and vaccines, was characterized by a semantic shi rom health toprevention to protection. In response to this shi, medicine had to assume theappearance o a biological technology.50 Canguilhem concluded that i medi-cine ever attained the status o a science, it did so in the era o bacteriology. Teresearch and development o remedies such as Emil Behrings diphtheria serum,

which involved large-scale sera production and regulation by government agen-


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Introduction 11

cies, was all based upon the use o bacteriology and hygiene as political tools osocial regulation.51 Hence, vaccines, sera and antitoxins in nineteenth-centuryEurope can be interpreted as boundary objects that not only exempliy the co-

productivity o the state, industry and science, but that also (as argued below)link physiology, the new eld o organic chemistry and alternative medicinemovements.52

Standardization and regulation were important characteristics o these newsubstances and the main ocus o American biologics legislation. AlthoughEuropean biologics were also discussed and regulated along similar lines, ocus-ing only on them is insu cient. While the history o vaccination and serotherapyin Europe has been explored at length in recent years, the conceptualization obiological substances is historically more complex and convoluted. One mustthereore trace a diferent path back to the long tradition o medicinal substances

prepared rom living organisms and compiled in the diferent pharmacopoeias.Medicinal substances prepared rom plants constituted an important part inthe materia medica literature. Although preparations rom animal bodies werealso integrated into the materia medica, their status was very diferent. Oen,traditional drugs were products that used animal parts, like dried viper esh,to prevent or counteract poisoning. Concrements rom goats stomachs alsothought to be efective against poisoning were not comprised o organic mat-ter in the modern sense, since they contained mostly minerals. Te same holdsor rasped or calcinated deer horns or corals. All these preparations entered into

the traditional tripartite classication o drugs as mineral, animal and vegetablesubstances.53 Preparations based on entire organs (livers, spinal cords, placentas)and body uids (animal blood) were also part o most pharmacopoeias.54 In thenineteenth century, authors like early pharmacologist Heinrich Bhnke-Reichtried to integrate regional German pharmacopoeias, thereby systematizing ani-mal and vegetable-based drugs (Arzneistofe aus dem Tier- und Panzenreich)according to pharmacognostic and chemical criteria. Te list ranged rom lardand staghorn to musk and cod liver oil and also included leeches.55 Bhnke-Reich was one o several authors who compiled items rom diferent German

pharmacopoeias in order to create a unied and modern body o pharmaceuti-cal knowledge. He retained the conventional, tripartite categories and includedtraditional remedies rom the vegetable and animal realms. Te entries reected

both traditional materia medica and new knowledge based on chemical andphysical methods. Many o these remedies, including a number o chemical com-pounds and new drugs, were listed in the rstPharmacopoeia Germanica (1872),the most important reerence work o pharmacists in the German Reich. Te

Pharmacopoeia Germanica, however, circumvented the problem o systematiza-tion by simply listing the substances in alphabetical order.


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But classications had already started to change with the development oorganic chemistry, which made it possible to produce organic substances outo inorganic ones. Te amous rst case was the synthesis o uric acid by Ger-man chemist Friedrich Whler in 1822. In the second hal o the nineteenthcentury, when cyclic compounds had come to be understood and later producedin the laboratory, organic chemistry began to branch of rom inorganic chemis-try, serving as a catalyst or changes in the systematization o the pharmaceuticalmateria medica. Te new chemistry helped to blur the distinction between theanimal and mineral realms by drawing on notions like ierchemie, the precursorto biochemistry, which was introduced by the German chemist Justus Liebig,and also by successully synthesizing organic substances that could be used inmedicine, such as chloroorm or acetyl-salicyclic acid.56 Proteins, amongst themthe enzyme pepsin, were marketed as substances to aid digestion.57 Unlike thechemical saga recounting the rise o the pharmaceutical industry, material med-ica was primarily composed o biologics and not chemicals.58 By the turn o thecentury, the vast majority o drugs used by doctors were prepared rom plants,

with little insight into their molecular structure or into the chemical propertieso active principles.59 Tis gradually changed with the emergence o biologi-cally active substances and new ideas o organic regulation. In this regard, its

worth reassessing the concept o biology itsel. As Foucault amously remarked,the concept o biology relied on an idea o lie itsel, on a unctional homoge-neity as its hidden oundation.60 Te new discipline o biology or lie science

(Lebenslehre) that was institutionalized in the 1850s was always more than justa counterpart to physics as a science o the inorganic world. More so than else-where, biology in Germany was shaped decisively by romantic and holistic worldviews.61 From the 1890s onward and on the basis o organological semantics, theadjective biological strongly connoted natural health, alternative medicine andthe new lie-reorm movement. Biological medicine (Biologische Medizin) wasboth Hippocratic rhetoric and body politics. In 1908, a medicinal-biologicalsociety (Medizinisch-biologische Gesellscha) was ounded, bringing togethernaturopaths, homeopaths, writers and artists, all o whom were critical o scien-tic medicine and advocates o holism. Te adjective biological signied notonly the knowledge production o an institutionalized scientic discipline, butalso an organological narrative that led to early twentieth-century biopolitics

positioning lie as the basis o politics.62

Biological medicine was not just a reaction to the so-called crisis o medicinein Germany, but also combined hereditary thinking with the utopian politics ohuman enhancement. In this regard, biological remedies were dened as thosenatural agents that protected bodies rom deciencies and so-called diseases ocivilization and that simultaneously enabled utopian visions o human enhance-ment.63 Notably, the physicians Erwin Liek and Karl Ktschau propagated a


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Introduction 13

holistic, precautionary liestyle that avoured preventive care (Vorsorge) insteado welare (Frsorge). Biological medicine combined prevention, eugenics andholism and translated a biological discourse into politics.64 In 1929, HeinrichMeng, a Viennese psychoanalyst and subsequent ounder o psycho-hygiene inBasel, compiled all the practices o biological medicine in his medical almanac(rztliches Volksbuch). Nine years later, the physician and entrepreneur GerhardMadaus (18901942) published a amous three-volume textbook o biologicalremedies (Lehrbuch der biologischen Heilmittel); and in1939, aresearch instituteor biological remedies (Forschungs- und Prungsinstitut r biologische Heilmit-tel) was ounded at the Paracelsus-Institute.65 Madaus products ranged romhomeopathic preparations o metals to hormones, enzymes or combinations obacterial antigens, but most o all plant derivatives. Such combinations o thera-

peutic agents, analysed according to their physiological efects, dosage, thresholdsand sensibility, were also ound in France in the 1930s, but there, restrained by thevisas des spcialits pharmaceutiques o 1941, herbalists lost their o cial status andcontrol o medicinal plants passed completely to pharmacists.66

Biologically active substances like organ extracts, hormones, vitamins andenzymes played a crucial role in lie-reormist discourse. In 1889, the physi-ologist Charles-douard Brown-Squard tested Claude Bernards assumptionsabout internal secretion in a spectacular sel-experiment, convincing him thatthe use o e cient substances produced by glands held out the promise o physi-cal rejuvenation. Brown-Squards so-called organotherapy was validated by

the British physiologist George R. Murrays successul therapeutic treatment omyxoedema with an active substance rom the thyroid gland o sheep in 1891.Te substitution, graing or re-implantation o glands substantiated the curativee cacy o certain internally secreted, but unknown substances.67 Around 1900,many organotherapeutics were in use and there was a common understand-ing o their e cacy: extracts rom endocrine organs were thought to replace a

patients ailing bodily unctions. When the British physiologist Ernest Starlingcoined the expression hormone in 1905, he had in mind very specic sub-stances that acted as chemical messengers speeding rom cell to cell along theblood stream and coordinating the activities and growth o diferent parts othe body.68 Likewise, the concept o vitamins as accessory ood actors ollowedthe logic o internal secretions and o e cient agents that could cure deciency

states. Hormones and vitamins were both drug-like and communicative sub-stances; they could be industrially produced while they dened and explainedthe modern body.69 Tis new physiology, based on problematizations o gen-der, sex, reproduction, nutrition and degeneration and situated in military andcolonial medicine, created a new concept o a homeostatic body regulated bychemical substances.70 o describe this class o substances, the German-speakingresearch community invented a term that ascinated not only researchers but


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also the general public in the 1920s: the aore-mentioned biologische Wirkstofe(biologically active substances).

Tis newly invented term was specically used to describe powerul, physi-ological substances such as hormones, vitamins and enzymes. In this context,chemistry and biology merged into a chemistry o natural substances (Natur-

stof-chemie) that brought chemical skills, biological knowledge and lie-reormistbelies together with the interests o the pharmaceutical industry. Te productiono biologically active substances was a pharmaceutical procedure, i.e. a chemical

process based on biological assays. During the rst third o the twentieth century,research on biologically active substances and the mass production o biologicalcompounds depended on the action o raw materials urine, testicles, adrenalglands, ruits and vegetables and the development o biological assays stabi-lize efectiveness and activate e cient agents. Te isolation o natural substancesrom animal organisms and the synthesis o bioactive molecules became the main

purpose o the highly productive cooperation between lie scientists and thepharmaceutical industry a cooperation that resulted in new molecules, patents,and a new physiology that seemed to hold great potential or enhancing the e -ciency o the human body. Te successul cooperation led to mass production ohormones and vitamins in Germany, Switzerland, England, the Netherlands andthe US.71 In a brie period rom 1921 to 1934, biological substances like insu-lin (1921), vitamin D (1927), estron (1929), androsteron (1931), ascorbic acid(1932) and progesterone (1934) were isolated and synthesized. Moreover, in the

rst hal o the 1930s, the list o biologically active substances and isolated naturalsubstances was expanded by unnatural synthetic derivatives.Vitamania and the rejuvenation craze were worldwide phenomena in the

1920s. But in German-speaking countries they took on special meaning becauseo their association with the lie-reormist concept o nature. Organs and the

various substances they secreted, as well as accessory ood actors, soon becamethe prime movers o biological medicine and public health policies involving

prophylactic practices.72 In Germany, research and development on biologicallyactive substances was part o the biomedical and political discourse. While thenew concept o a biological body, clearly dened by natural laws, was the basisor Nazi Germanys biopolitics, Wirkstofe as drugs with a seemingly vital abilityto strengthen human e ciency came to play a central role in National Socialist

war policies.73

Biological medicine, organized in Nazi Germany as a New Ger-man Terapy(Neue deutsche Heilkunde), deeply inuenced German concepts ohealth or over hal a century and well into the post-war years.74 Biological rem-edies, biologically active substances (Wirkstofe) and vital substances (Vitalstofe)all held out the promise o sound health, an organological and natural way oliving and a biological identity.


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Introduction 15

Te Widening o the Concept o Biologics: Te Biotechnologicalransition until oday

Te decades aer the Second World War, especially rom the 1950s to the 1980s,were dynamic years or biologics, as the number and variety o biologics aswell as the challenges acing regulators continued to grow. Especially whenrecombinant drugs emerged on the market, scientists, regulators and the publictended to treat them as new kinds o substances that became denoted as biologi-cals. However, this transition, which was oen labelled as a biotechnologicalrevolution, neednt be viewed as something entirely new, but rather as a recent

variation in the episteme, technology and economy o biologics. Te colossal

change in our abilities to use and appropriate living organisms, as Gaudillireclaims, started much earlier than common narratives o the so-called biotechno-logical revolution proclaim.75

Aer the spectacular introduction o penicillin in the 1940s, the biotech-nological exploitation o ungal metabolisms invigorated the search or magicbullets.76 Likewise, the amazing efects o the hormone cortisone raised expec-tations and drove pharmaceutical industries in their search or initial extractsrom exotic plants.77 Another advance in post-war research that signicantlyinuenced the development o biologics was made in 1949 at Boston ChildrensHospital, where scientists successully grew a human virus, the Lansing ype II

polio virus, in a human tissue cell culture.78 Te ability to grow human viruseseasily and saely outside o a living host wasnt just a breakthrough that led to anexplosion o research in vaccinology, but also a precondition or discoveries andchanges relevant to biologics in the second hal o the twentieth century.79 Fromthe 1950s onward, vaccine research ourished. In the mid-1960s, pioneering

work resulted in the rst experimental live virus vaccine against German mea-sles (rubella). est inoculations conducted in West Arica led to a combinedmeasles-smallpox product, the rst commercial combined live virus vaccine.80Te growth o industrial biochemistry also established important prerequisitesor the biotechnological transitions. Te late 1960s and 1970s brought about arevival o interest in enzymes and their applications. Enzymatic reactions hadbeen in use or some time, but now they began to play a central role in certainbranches o production and triggered new developments. Increasingly, biologi-

cal agents became recognized as an important eld o uture research.81

Te new technologies were also subject to regulation, especially inasmuch asbiologics were employed in ood production or conservation. Te ood industrymade increasing use o enzymes and enzymatic systems that were biotechnologi-cally produced rom non-toxic micro-organisms. Te Joint FAO/WHO FoodStandards Programme thereore included enzymatic preparations in its compre-hensive eforts to develop ood standards and codes o practice.82 But the use o


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biologics or ood preservation also raised concerns. Pharmaceutical rms began tomassively promote the use o antibiotics as preservatives in resh ood.83 Althoughattitudes towards this practice difered rom country to country, West Germanregulations completely banned the use o antibiotics as ood preservatives in 1958.

Tese developments not only changed the meaning o biologics, but alsothe ways o handling them. Te ate o the Division o Biologics Standards,

which stood at the centre o the re-organization o the NIH in the US, is a casein point. In 1955, aer the so-called Cutter incident involving the deaths oeleven people due to an impure polio vaccine sold by Cutter Laboratories, thestatus o biological control within the NIH was improved: to strengthen andexpand its operations, the Division became an independent entity within theNIH.84 Around 1970, the Divisions review activities were criticized or notbeing as well institutionalized and not as clear and efective as the equivalent

work being perormed or the control o medicinal drugs.85 And in July 1972,both the authority to administer the drug provisions o the FD&C Act or allbiological products and the responsibility or implementing the Biologics Act

was delegated to the FDA.86 Te Division o Biologics Standards was transerredrom the NIH to the FDA and renamed the Bureau o Biologics (BoB). In onesense, the merger with the FDA was a oregone conclusion because a biological

product as dened by the 1944 PHS Act also ell within the jurisdiction o theearlier 1938 FD&C Act. Tus, the jurisdictional and regulatory provisions othe 1902 Biologics Act and the FD&C Act were combined under one authority.

When the BoB was merged with the FDA Bureau o Drugs in 1982, the evalu-ation o drugs and biologics was bundled into one institution, the NationalCenter or Drugs and Biologics (NCDB). Te FDA journal, FDA Consumer,sought to justiy this merger as early as 1977: Vaccines are just one o a group odrug products that are called Biologics because they are made rom or with theaid o living organisms that are produced in man or animals.87

Tese changes in institutional organization reected major scientic changesrelated to the beginnings o the biotechnological transition in the 1970s. Inshort, the distinction drawn between a drug and a biologic, or a device and abiologic, became ever more blurred.88 Contemporary denitions o biotech-nology ocused attention on the biotechnological processing o biologicalagents in general, even though they were initially intended or industrially use-

ul enzymes.89

Hence, biotechnology was already attracting increased attentionwhen the next step in its development occurred, i.e. when recombinant DNAtechnology appeared on the scene in the 1970s.

With the advent o genetic engineering, the modication o micro-organ-isms opened up new possibilities in industrial processing, agriculture andbiomedicine. Te biotechnological production o clinically relevant moleculesbecame the main challenge aced by early biotech companies in the 1970s and


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Introduction 17

1980s. Geneticists such as Joshua Lederberg time and again emphasized thepotential benets o genetic engineering.90 Some o the urther steps in thedevelopment o genetic engineering have been well researched.91 Insulin wasone o the proteins that embodied the aspirations o the New Biology and its

promise o new products. A team at the University o Caliornia, San Francisco,associated with Herbert Boyer, who in April 1976 ounded the small companyGenentech (Genetic Engineering echnology), used the bacterium Escheri-chia coli to produce insulin and claimed success in September 1978. Te FDAnally approved the drug in 1982. Despite the claims that molecular biology

would revolutionize the whole industry, the main ocus o attention aer insu-lin turned to other potential money-spinners: human growth hormone andintereron, a protein that the body itsel produces to ght viruses and that thus

promised to be a miraculous cure or viral diseases. By 1980, Biogen was produc-ing intereron through recombinant DNA aer human DNA was transerredto bacterial DNA.92 In the case o intereron, the promised magic bullet in theght against viral inections never materialized and several companies shiedtheir attention elsewhere.A new, immunologicalapproach emerged, based oninterleukin-2, which was hailed as the new natural weapon against cancer.93As Pieters summarizes, such substances represented a process o molecularizingmedicine that originated in the engineering, preparation and purication o so-called recombinant protein drugs.94

Retrospectively, the transgenic transormation o biotechnology rom the

1980s onward has been interpreted as a major break, either in terms o politics,technology and research practices, or in terms o the mode o knowledge pro-duction.95 Tis rupture ound expression in the prolieration o a term used todenote the recombinant DNA products: biologicals. Te WHO began to usethe term biologicals exclusively aer its department o biological standardiza-tion was renamed biologicals in the mid-1970s and rom the 1980s onwardsthe term was used only in connection with advances in biotechnology and newbiological products prepared using recombinant DNA techniques.96 Generally,the common term biologicals came to be associated with the biotechnologi-cal age o recombinant DNA technology, while the term biologics was moreclosely a liated with the regulatory context o traditional biological substancessuch as vaccines. In his history o the FDA, Carpenter points to the simultane-

ous and sometimes conusing use o both terms ever since that period:Molecular entities are usually distinguished rom biologics. Te world o biologics isoen wrongly conated with the world o biotech, when in act most biotechnologydrugs are not vaccines or otherwise bioactive. A more pervasive diference is betweensmall and large molecules, such that the larger molecules represent proteins andantibodies that are biologically active whereas the smaller molecules stand in ormore traditional drugs.97


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However, this distinction represents only a snapshot in the history o biologicsand their denitions. As in the story o intereron, there was no clear-cut breakbetween conventionally produced substances and the substances o the biotechtransition since both originated in the preparation and purication o biologi-cal material.98 Likewise, since the 1980s, the terms and classications have againbecome contested, reecting the challenges o regulation and developments inthe biotech industry. By 1988, ve proteins rom genetically engineered cells hadbeen approved as drugs by the FDA: insulin, human growth hormone, hepatitisB vaccine, alpha-intereron and tissue plasminogen activator (tPA) or lysis oblood clots.99 In a reaction to this slow progress, research policies in the US andin Europe began developing new strategies.100 Tis shi was described in a 1990report o Britains science advisory committee ACOS: Whereas eforts so arhave been concentrated on the generation o biologically important molecules,the next phase is likely to lead to the engineering o higher levels o biologi-cal organization: the engineering o pathways and cells.101 Tis new situationhas contributed to ongoing negotiations about the very denition o biologics,

which in turn has been reected in the steady reorganization o regulatory bod-ies. In 1988, the FDA again split biologics rom the more general drug review

process.102 Since then, the FDA has been busy distributing and redistribut-ing the responsibility or an ever-growing number o biological products. TeFDA Center or Biologics Evaluation and Research (CBER) became responsi-ble or some therapeutic proteins, such as monoclonal antibodies, but control

o these was later transerred to the Center or Drug Evaluation and Research(CDER).103 Some other drugs, such as certain anticoagulants and plasma vol-ume expanders, have remained under the control o CBER. Meanwhile, thelist o biologics continues to grow, including not only new substances but alsocell products and organs such as human cell tissues, xenotransplantation, genetherapy and human cloning.104 Similar ongoing redenitions and regulatoryreorganizations occurred in Europe as well. Te rst European pharmaceuticaldirective o January 1965, Directive 65/65/EEC 1965, provided only a roughsketch o eforts to harmonize European drug regulation and listed a range osubstances, including a variety o biological products derived rom human, ani-mal, vegetable and chemical sources.105 Tis list was updated some thirty yearslater when the London based European Agency or the Evaluation o Medicinal

Products (EMEA) set up 1995 and later renamed as the European MedicinesAgency, EMA established a Biologics Working Party (BWP) to provide rec-ommendations to the EMA scientic committees on all matters relating toquality and saety aspects relating to biological and biotechnological medicinal

products.106 In 2001, the European Union updated the 1965 directive to includea rearranged list o biologics that reected the new system o drug approval. TeCommunity code relating to medicinal products or human use diferentiates


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Introduction 19

our approval procedures. Notably, the various biological products were notgrouped into one category, but distributed across all our categories dependingon the specic characteristics o the medicinal approval process.107 However, onehas to be careul with all these denitions since the terms and uses depend onthe legislative and the administrative context. For instance, while the EMA di-erentiates biologics and biologicals (biotechnological medicinal products),the Directive 2001/83/EC does not reer to biologics at all; instead, it usesthe somewhat analogous terms biological medicinal products and biologi-cal medicines respectively.108 Even more conusingly, additional terms such asbiomedicines have come into use with the prolieration o biologics, agencies,markets and with practices related to biological products.109

Te realm o biologics has evolved throughout the twentieth century and themetamorphosis o objects and concepts remains unnished. In the uture, we

will see more substances and new classes o substances enter the stage and changeour understanding, classication and regulation o biologics. One very recentexample is the advent o biosimilars, i.e. the analogues o generics in the eld obiotechnologically produced medicines. Future work may reveal more details othe semantic eld o biologics and dig deeper into linguistic and conceptual lay-ers and transitions such as the biotech transition. But or the moment, what can

we learn rom this overview?

Biologics in the History o Medicine, Pharmacy and Science

Tere is no easy, apodictic way to determine the object o biologics studies. Teprevious sections have examined biologics as a semantic eld containing difer-ent denotations, such as natural substances, Naturarzneien, organotherapeuticsubstances, Wirkstofe, biological products, biologics, biologicals, mdicamentsbiologiques, biopharmaceuticals and biological medicinal products. Such diversenomenclature reveals that the history o biologics is truly multiaceted anddi cult to grasp. Generic terms such as biologics and biologicals played animportant role in the US, whereas European scientists and regulators were reluc-tant to adopt them. In Germany, the term biologische Wirkstofe was introducedin the context o hormone and vitamin research, but it signied somethingquite diferent compared to the regulatory environment in the US, where theterms biologics or biological products included allergens and immune-based

products, but not hormones.110 And so, as the semantic overview suggests,attributions have been made according to actual and practical needs, orcing his-torians o medicine and pharmacy to account not just or the common eatureso biologics, but also or their specic historical development. For instance, theconcepts o mid-twentieth century pharmacy cannot adequately explain whyarsphenamine a class o arsphenical substances was subjected to the Bio-


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logics Control Act 1944. Most probably this was due to the act that it posedregulatory problems analogous to sera and vaccines and was equally important,since it was administered in the ght against syphilis.111

But how can we dene biologics when the categories in the semantic eld havebeen blurred throughout history? Biologics have been dened in terms o sources,chemical properties, immunogenicity, macromolecular size or structure, or unc-tion. Tey have been characterized as complex macromolecules, as proteins, asderived rom living organisms, natural sources and so on. In his splendid analysiso the language o biologics, Korwek stepped into deeper waters in analysing cat-egories such as use, mechanism and origin as the shiing points o reerence orregulatory denitions over time. For instance, use was an important aspect ooriginal statutory language that ocused on disease prevention. Te preventionand cure o diseases language o the 1902 human biologics statute was revised in1944 to include the prevention, treatment, or cure o diseases or injuries o mansince injuries had become the main rationale or blood transusions during theSecond World War.112 Korweks analysis o the language o biologics once againemphasizes the signicance o the practical historical context or the denition obiological products. What people denoted as biological products, biologics, orbiologicals was embedded in the context o regulation and legislation.

Te language o biologics reveals these substances as cultural, political,economic and socio-technical entities. Biologics are at the same time naturalresources, experimental representations, technical devices, visions, products,

medical and clinical measures, cultural practices and legal entities. In act, someo the historical approaches we considered in the previous section already sug-gest as much. ake or example an amendment to the directive o 2001, in whichthe EU Commission eventually tried to dene biologicalproducts. Notably, thisdenition did not explain what biological products are as a group o substances,but instead described a eature that they share: what biologics have in commonis the act that they are made out o any substance o biological origin.113 Forinstance, biologics such as vaccines are substances produced in highly elaborated

procedures o maceration, ltration, digestion, distillation, evaporation, sterili-zation, desiccation, levigation, dialysis, precipitation and physiological assay oliving organisms. By adopting a pragmatic approach towards the history o bio-logics, the authors o this volume avoid ontological presuppositions about the

nature o biologics, ocusing instead on the technical context o biologics andthe way they are produced. Synthetic drugs consist o pure chemical substancesand their structures are known. Biologics, however, are complex mixtures thatare not easily identied or characterized.114

Tese conceptual insights can be incorporated into a characterization o bio-logics as substances that (1) are specic kinds o drugs, (2) have a biological


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Introduction 21

origin, (3) are processed and (4) are more complex than drugs in general.115 Forthe purposes o historical analysis, it is important to emphasize that this is nota characterization that relies on any putative nature o biologics, but insteadsimply a helpul heuristic tool or use within an ever-changing common eld ohistorical objects. Hence, none o these our traits are timeless and there are sub-stances that do not satisy these criteria. Te ollowing examples illustrate some

pitalls: rst-generation antibiotics were described as any substance producedby a micro-organism that is antagonistic to the growth o other micro-organ-isms. With advances in medicinal chemistry, most o todays antibacterials aresemisynthetic modications o various natural compounds. Tere are diferentclassication systems in use or antibacterial compounds, based either on theirorigin, their mechanism o action, their chemical structure or their biologicalactivity. Again, we are conronted with the question o what biological originmeans. Te case o the synthetic drug DES (Diethylstilbestrol) also belies easydenition. In the 1950s, DES was used in arming in spite o debates about thehealth risks it posed.116 Te pharmaceutical industry invented DES as a medicaltreatment or certain conditions, including breast and prostate cancers. It was notuntil the 1970s that DES was ound to be an endocrine disruptor, i.e. a chemicalthat intereres with the hormone system in animals and humans.117 Tese andmany other examples illustrate that origins alone do not su ce in transormingsubstances into biologics.118 Tey show that the eld o biologics is historicallydetermined and actualized by experimental congurations and trajectories, dis-

courses, marketing strategies, regulatory practices and legal denitions.Biologics studies will contribute to the history o pharmaceuticals and medi-cine in as much as they illustrate the epistemes, cultures, policies and economies oconnections and demarcations that constituted biologics as specic kinds o drugsand, hence, as historiographic objects in their own right. Tese studies will drawon the histories o individual substances to teach us more about the specic rela-tionship between biologics and politics, science, industry and culture. Althoughthis introduction ocuses mainly on regulation and legislation, the history obiologics is not limited to these contexts. An impressive number o excellent casestudies have already been published that examine biological substances as objectso scientic inquiry, the pharmaceutical industry, public health policy and reormmovements. We thereore advocate a comprehensive perspective that will stimu-

late uture work and that will incorporate a panoply o connections to the storieswe tell about the development o single substances such as diphtheria serum, vita-min D, estrogen, or intereron and their characterization as biologics.

Te essays published in this volume suggest three main domains that con-tributed to the shaping o biologics as economic, political, social and culturalobjects and that are best suited to grasping the historicalcontingencies o theseheterogeneous substances and materials.


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Tese domains, which constitute the organizational structure o this book,are (1) the production o nature, (2) the body politics o biologics and (3) themaking o contested biologics.

Te Production o NatureTe rst part o the book ocuses on one o the basic problems o drug pro-duction and on a undamental technique o the modern industrialized world:standardization. Standardization became a key part o the research, productionand regulation o pharmaceutical chemicals and was thereore an importantconcern in the nascent market or modern drugs rom the nineteenth century

onwards.

119

In the history o biological products, the standardization and regula-tion o vaccines, sera and antitoxins have garnered the most scholarly attention.120Standardization was usually equated with the development o reliable bio-

logical assays. Up to the present day, these assays have been major targets oindustrial as well as administrative orms o regulation. Both the variability othe biological raw material and the uncertainties regarding the composition oextracts made standardization essential, but di cult. It is no coincidence thatthe early strategies oWertbestimmungcombined statistical procedures with eas-ily observable phenomena (e.g. the percentage o deaths prevented by a certainquantity o serum in a given animal population). Experiences with biological

products have repeatedly resulted in their impure origin rom nature beingproblematized. o name just one early, prominent case: in the 1850s, the French

physiologist Claude Bernard tested extracts made rom strychnea by diferentParisian pharmacies and came to the conclusion that they difered by a actor osix.121 Successully isolating a hormone or vitamin, enabling an adequate chemi-cal method or its measurement and synthetically producing the pure principleall involved the use o biological tests and, hence, standardization. As British

pharmacologist Henry Dale proclaimed, the only property by which an activeprinciple can be recognized and measured is its action on the living animal orisolated organ, which must somehow be made the basis o what is called a bio-logical standardization or biological assay.122 Questionable purity and theequivocal results o clinical observation are oen two sides o the same coin.Te story o anti-diabetic agents derived rom plants leads directly to the prob-lematic qualities that, time and again, are ascribed to biologics. And it illustrates

how the model o biological efects served as a bridge linking pharmacognosticaland biochemical plant research with animal and clinical studies. In general, the

pharmacological efects o biological preparations lacked reliability.123Te point here is that the problems posed by biologics were associated with

particular orms o production that included not just standardization (the bio-assays), but also characteristic routes o production (extraction, ermentation,or enzymatic synthesis), and a special legal status.124 Te specicities o biologic


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Introduction 23

production shaped science, industry and regulation. In most European countries,therapeutic agents were not patentable. When the German pharmacopoeia wasenacted in 1872, the normal objects o drug regulation were still considered tobe pharmaceutical substances produced according to the rules o the pharmaco-

poeia. But a number o new substances were already being manuactured outsidethe pharmacies, which merely inspected and tested them, and so their synthesis

was not described by the pharmacopoeia. Patented medicines with secret ingre-dients were also marketed. Most biologics were not included in the traditional

pharmacopoeias because there were no generally accepted verication proceduresand pharmacies were oen unable to conduct appropriate testing. Te realm o

pharmaceutical biological drugs witnessed the introduction and tentative imple-mentation o several orms o patenting and intellectual property rights protection.

In his essay on the introduction and production o diphtheria serum inFrance,Jonathan Simon argues that what set sera apart rom patent medicines

was their intimate connection with the promise o innovative scientic research,notably in microbiology. Te special status o biologics was based on the precari-ous qualities generally assigned to them. Contamination was the rst di cultyascribed to the production o biological products. As they were derived romliving organisms, this procedure brought with it the potential or the transmis-sion o inectious diseases. In 1927, the US o ce o biologics control concluded:

Te products covered by the law and regulations viruses, serums, toxins, antitoxinand analogous products applicable to the prevention or cure o diseases o man are

collectively reerred to as biologic products and by their very nature are particularlyprone to become contaminated, or, in some instances, rapidly to lose their curativeproperties. It was because o these peculiar properties o this class o products that thenecessity or some method o accurate control o their manuacture and sale was earlyrecognized.125

Te need or purity in research, production and control evoked an apparatuso practices and acilities that acilitated standardization. Purity was a time-consuming and expensive necessity in the production o biologics. Producingisolated or synthesized substances on a large scale became a question o tech-niques, patents and costs. Last but not least, this transormation into a remedy

was determined by economic and material constraints.Research as well as commercial production o biologics depended on the use

o natural resources, requently in very large quantities. An oen-cited exam-ple is the production o extracts and hormones out o tons o animal organsacquired rom slaughterhouses. In most cases, however, the trajectories o bio-logics were interconnected with colonial history: the exploitation o resources,the appropriation o indigenous knowledge and the transormation o both intoan industrial context.126 As described in Jean-Paul Gaudillirescontribution,


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the invention o drugs rom extracts o kola nuts grown in sub-Saharan, tropi-cal West Arica depended on colonial economies and politics. He concludesrom his case study that kola extracts became drugs elaborate, albeit impurecompositions only once a series o practical and social arrangements had been

perormed: Biologics were not just remedies made out o biological things.Tey were technical objects, at once socially and culturally associated withnature and at the same time elaborated through industrial mass-preparation.127

Another obstacle that has oen been highlighted as a common eature obiological products is their complexity. Biological products are more di cultto identiy and characterize than chemical products, and accordingly it is moredi cult to ensure that their identity remains unaltered under diferent manuac-turing conditions. Te FDA has thereore customarily required clinical testing oany product manuacturedat a new site beore it will license production there.128A recent denition o biologics makes reerence to these problems: In contrastto most drugs that are chemically synthesized and their structure is known, mostbiologics are complex mixtures that are not easily identied or characterized.129oday, more and more modern biological products can be standardized usingchemical analysis and there are numerous attempts being undertaken to pro-duce biologics in the same way that other pharmaceuticals are made. Tereore,some proponents argue that biologics should no longer be generally consideredas complex mixtures.130 Nevertheless, complexity has shaped the production obiologics, rom research on the mysterious efects o extracts and the industriali-

zation o these substances to the regulatory mechanisms governing them.Standardization and problems arising out o the production o biologicsbecame keystones o specic social, legal and commercial congurations. Somesera like antidiphtheric serum were standardized in Germany, but they werenot subject to drug legislation around 1900 because they were not marketedthrough pharmacies. Instead, special laws regulated them. As mentioned above,the production procedures o some standard, industrially produced chemical

preparations were or the rst time no longer dened in the pharmacopoeia.Tus, the advent o biologics coincided with a major shi in medicinal culture.Te question o who controls and markets which substance has continued tobe a bone o contention up to the present day, and it always hinges on legal andscientic categories. From the outset, regulatory bodies such as the US Public

Health Services Hygienic Laboratory ocused on biological standardization.131

Furthermore, the unolding o standardization strategies should be analysedas social and economic processes that inuenced both the substances and the

protagonists involved, thereby also afecting research and the drug developmentprocess, as well as the wider social context.

For instance, shortly aer its establishment in 1921 and under the presidencyo Torvald Madsen, Director o the State Serum Institute in Copenhagen, the


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Introduction 25

League o Nations Health Organization declared that establishing standards orbiologicals was one o its most urgent tasks.132 In 1921, it initiated a meeting ointernational experts that nally agreed on Ehrlichs unit or diphtheria antitoxinand arranged or the production o an international standard preparation to bedeposited in Copenhagen.133 Tis conerence was ollowed by urther meetingsin 1923 and 1925 to discuss digitalis, pituitary posterior lobe extract and insulin,in 1931 to nd stable standards and dene units or vitamins and in 1932 and1935 to speciy biological tests, names and units or sex hormones. 134 Interna-tional standard preparations or oestrus-producing hormones, androsterone and

progesterone were kept at the National Institute or Medical Research in MillHill on the outskirts o London. It can be argued that these activities, based asthey were on the generic problems o biologics, inuenced the health-care poli-cies o the League o Nations in general and that the Leagues StandardisationCommission became an important means by which the League advanced itsagenda o peace through international cooperation.135

Later on, biological standardization certainly became one o the mainconcerns o the WHO: to date, the WHO Expert Committee on BiologicalStandardization has published 59 reports. And it has cooperated with nationalagencies like the Division o Biological Standards o the National Institute oMedical Research in London in its work on intereron.136 Te history o inter-eron is an example that illustrates how, in spite o improvements in both the

production and regulation o biologics, the problem o standardization remained

rampant, because, as in the case o many other biologics, puriying the substanceand establishing its biological denition proved especially challenging.Te process o standardization was not just a scientic and technical proce-

dure, but also deeply entangled with social and economic actors and interests.Standardized products shaped and were shaped by this heterogeneous cluster oscientic practices, social actors, material structures, administrative routines andthe industrial logic o valorization.137 As mentioned above, historical studies onbiologics have to take into account the institutionalization, regulation, activa-tion and casual use o these agents. From this perspective, their standardizationhas been multiaceted, involving diferent kinds o laboratory, economic andregulatory standards. Absolute control was more o an ideal than a reality andsome o the contributions to this volume ocus on experimental systems and the

di culties encountered while attempting to stabilize biological material. As LeaHallershows in the case o cortisone, the procedures or standardizing and puri-ying biologics would sometimes destabilize the entire experimental system andthereby efect a change in therapeutic rationale.138 Te process o stabilization,activation and processing o biologics modied experimental systems as well asthe social and economic conditions o their use.


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Te Body Politics o BiologicsTe second part o this volume considers the use o biologics in various orms ointervention in the human body, as well as their impact on the creation o bodilyconcepts. Biological substances enabled new ways o intervening in undamentalbodily processes and provided new options or bodily perection and humanenhancement. We assume that the ambiguous character o biologics viewedboth as chemical agents, technical objects and matters o natural origin hada major impact on their production and commercialization. Te transorma-tion o natural substances into pharmaceuticals, which was the subject o publicdebate and was shaped by the inuence o several interest groups, was a major

task in the early twentieth century. Standardization, regulation and activation obiologics should thereore be analysed as scientic and political discourses andpractices that connect molecules and organisms in a historically specic regimeo knowledge and power.

In illustrating this point, vaccines, sera and antitoxins are again a good placeto start. Te initial successes o bacteriology in the 1890s called into serious ques-tion the undamental paradigms o medicine. Bacteriological knowledge becamea new ramework in which to conceptualize not only the causes o diseases, butalso the relationship between the human body and its environment. Bacterio-logical knowledge was a battleeld o contagion and the bodys own deences.139Te body was an irritable machine, both physiologically and mechanically, rom

which hygienic knowledge and strategies could be derived.140 Hygienic strategies

targeted both the environment and individual behaviour (washing ones hands,using a handkerchie ). Te individual that preerred health as an aim in lieand thereore submitted to medical-scientic principles the homo hygieni-cus was a scientic construct o bacteriology.141 Tis body politics o sel-care

was enacted through governmental surveillance and health-care policies, mostprominently in the orm o vaccination programmes that aimed at the bodysphysiological deences. Substances derived rom biological material sometimesplayed a decisive role when new representations o the body intermingled withbody politics, as in the case o Sigmund Freuds coca studies. Freud used theamous dynamometer to transorm the Indian habit o chewing coca leavesinto a measurable efect o cocaine on the modern, working body. As Beat Bchiargues, Freud thereby linked the consumption o cocaine to emerging modern

concepts o atigue and to norms o the productive body. Te power o biologi-cal substances to activate the exhausted body urther elucidates the relationshipbetween the production and commercialization o biologics on the one hand,and body concepts on the other. From this perspective, the emergence o difer-ent types o biologics around 1900 triggered a commercial success story, linkingthe ates o new biological molecules like cocaine and cortisone with the prom-ises o organotherapy.


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Introduction 27

From the 1920s onward, concepts o biological regulation acquired moreand more chemical connotations. Te complex interplay o antagonistic andsynergistic chemical reactions and chemical metabolism justied hormone or

vitamin therapies. Up until the mid-1930s, the isolation o natural substancesrom animal organisms and the synthesis o bioactive molecules provided theraison detre or a highly productive collaboration between lie scientists and the

pharmaceutical industry that produced numerous molecules, patents and a newphysiology that seemed to hold great potential or enhancing the e ciency othe human body. Te aim o reshaping or even rejuvenating the body was basedon the experimental physiological use o organs or nutrients to compensate ordeciencies.142 But only biologically active substances (biologische Wirkstofe)that could be extracted and chemically synthesized (such as hormones and

vitamins) were able to transorm this area o research into an industrial and com-mercial project. Heiko Stofs overview o this eld o research and its historiesshows that the isolation o biologically active substances combined knowledge

production about the body with the activation o natural products and theirtransormation into pharmaceuticals. In pledging to produce e cient bodiesand to protect consumers rights to tness, health and youthulness, hormonesand vitamins were decidedly modern and in some respects even a catalysto modernity. In this regard biologics not only merged laboratory research andindustrial production, but also linked practices o representation and interven-tion. However, research and development on biologically active substances came

along with a new biological body, clearly dened by natural laws. In Germany,this concept became the basis or Nazi Germanys biopolitics. Wirkstofe as drugswith a seemingly vital ability to strengthen human e ciency played a central rolein National Socialist war policies.143

Te natural option became a central theme o body politics that targeted theexhausted and decient body. Tat body can be described as being both indus-trial and non-industrial because one has to diferentiate between the culturalreservoir o meanings associated with biologics as opposed to industrial strate-gies and calculations. Te marketing o biologics as therapeutics or prophylacticsand the new physiology o an organism regulated by chemical agents share thesame origins. Even though biologics have long been articially and/or industri-ally produced, they have retained their image o being more natural than drugs

synthesized rom inorganic substances.144

Te twentieth century witnessed thecreation o new consumers o biologics and brought orth markets that weregrounded in a discourse about naturalness, lie and vitality.

Tis understanding o biologics as natural substances continued into thelate twentieth century, when a new wave o biologics arose that relied upon bio-technologically produced materials. For instance, although company o cialso Wellcome, Roche and Schering-Pough had di culty deending the costly


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intereron research and development, they were ultimately successul in depict-ing intereron as an opportunity: unlike most chemical drugs, these geneticallyengineered biologics could be viewed in their natural (physiological) role asregulators or modiers o a variety o pharmacologically interesting biologicalmechanisms.145 Biomedical technologies not only evolved new options in therealm o molecular biology, but also in the handling, treatment, storage andapplication o bodily organs, tissues and cells. Like the technical transormationo cell mechanisms into engineering tools, these new biologic regimes turned thehuman body into a resource o biological treatment.

In his ethnographic study o the procedures o assisted reproduction, SvenBergmann ollows the transormation o body parts and the making o reproduc-tive substances using procedures like purication, preparation and classication.At the same time, these objects are loaded and attached with meaning andallusions that remind us that living material has a separate social lie. SophieChauveau tackles the process that transorms human body parts into organ andtissue transplants. Her analysis is linked to themes rom the rst part o this vol-ume and presents an analysis o standardization as a process o change: humanbody parts are transormed into products, like drugs or surgical equipment, andthen into commodities. But there are diferences, because like tissue or entireorgans, human body parts are more akin to living things than biologics in thenarrower sense. Tis conclusion may point to essential problems that accompanyorgan transplantation, since this medical practice depends on a radical shi in our

understanding o what a living body is and what living means in this context, asillustrated in debates about the brain-death criterion. Hence, organ transplanta-tion is a contentious political issue that brings us to the next part o this book.

Te Making o Contested BiologicsTis nal section addresses another basic aspect o biologics: their precariousqualities. Modern pharmaceuticals are well known to have potentially deleteri-ous efects. Indeed, most o the substances discussed in this volume have theirown ambiguities in so ar as their efects can oscillate between desirable andharmul outcomes. A common way o reerring to these problems is to speako side efects. However, this term disguises the act that harmul efects arenot an accidental quality, but rather a basic eature o modern pharmaceutical

research.146 Tis holds or drugs in general, but it is especially pronounced in thecase o biologics since these problems seem to be specically connected to theirhistorical characterization. We have already argued that the basic qualities con-tinually being ascribed to biologics tend to evoke specic problems: it is di cultto appropriate them within laboratory regimes, to stabilize their efects and tostandardize their production. As Pieters concludes in his story o intereron: Asar as the pharmaceutical industry was concerned most biologicals had a prob-


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publicly debated and negotiated, not least because it involved consumer interestsas well as lie-reorm discourses. In this vein, studying risk management bringstogether the history o consumer culture, public problematizations o naturalsubstances and scientic denitions o risks. Biologics might have been risky andin need o trials to ensure their e cacy and saety, but they could also unctionas a surrogate or nature gone missing. In so ar as biologics difered rom chemi-cal compounds due to their epistemological status as natural substances, theytransported discourses o purity, naturalness and vitality. Te juxtaposition onatural and articial substances not only inormed public discourse on healthybiologics such as plant products, organotherapeuticals or vitamins versus riskysynthetic pharmaceuticals, but also inuenced scientic debate and practiceitsel. As we have argued in this introduction, the shis and conicts within thediscourse on natural substances or on their naturalness have persisted to thisday, since those substances have always been both biological and chemical, bothnatural and synthetic.

One o the early examples o this can be seen in the history o the publicsconcerns about vaccination. Te animal origins o the inoculating agents wasone o several acts that evoked public concern. Ideally, smallpox vaccination

was derived rom well-tested cal lymphs. Tis seemed to juxtapose animal sub-stances and human lives, and the image o organic substances rom diferentspecies being mixed with the human body elicited deep anxieties. But becausecal lymphs were scarce and di cult to store, vaccination was also perormed

rom arm to arm.153

Yet, the transer rom human to human raised apprehen-sions as well, since numerous cases o inection most prominently with syphilis were known to have occurred. In both Germany and England, vaccination

programmes provoked vehement protests on religious, political, scientic andmoral grounds. Should healthy people, notably children, be put in jeopardy ocontracting an inectious disease or sufering harmul side efects? Aer severalepidemics in the early 1870s, statistics provided evidence or both proponentsand adversaries o compulsory vaccination. Te death toll seemed to be as highin populations that had been almost completely vaccinated as in those that hadnot been. German legislators reacted by making not only vaccination, but also re-

vaccination aer ten years compulsory, whereas in England the ongoing debateabout compulsory vaccination resulted in the 1898 act allowing a large percent-

age o the population to opt out o vaccination. Here, a policy that relied more onlocal public health administration than on vaccination, won the upper hand.154Tis was in line with the strong European hygiene movement that demandedepidemiological studies and strategies that ocused on the environment ratherthan the body. Long beore the amous Lbeck scandal o 1930, when over sev-enty babies died rom a tuberculosis vaccine that had been contaminated with

virulent bacteria, vaccination had become a bone o contention.155


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Introduction 31

Te invention o biologics brought with it scepticism, protest and ear. Whilevaccines and sera were too biological and raised doubts and anxieties aboutpurity and contamination, synthesized hormones and vitamins were too chemi-cal and elicited concerns about toxicity and alienation.156 However, biologicsalso became contested as natural resources originating rom countries with longcolonial and imperial histories. Colonial and imperial possessions were used assources o natural products that could be developed into biologics, such as theStrophantus species rom West Arica, sisal rom East Arica and yam (Dioscorea)rom Mexico that were used in cortisone production.157 Tere is an enormousliterature on these kinds o material relations that, in act, brings together topicso imperial exploitation o the natural world and the history o biologics.158 Tatliterature demonstrates that access to certain substances has been a key actor inthe relationship between botany, commercial activities and politics, somethingthat hasnt changed to this day.159 Between 1991 and 2003, pharmaceuticalcompanies annually imported 467,000 tons o medical plants rom twelve devel-oping countries or use in the production o plant medicines.160 With the rise othe New Social Movements and the internationalization o nature conservation,these companies have become embroiled in the politics o colonial and imperial

power relations. Te last contribution to this volume ofers an example o thepoliticization o assembling practices. Klaus Angererocuses on the trajectoryo epibatidine, an alkaloid isolated rom poison rog skins that had been col-lected during several eld trips to Ecua

Documents

Introduction to Biologics, A History of Agents Made From Living Organisms in the Twentieth Century