History of Biotechnology

Robert Bud, Science Museum, London, UK

Biotechnology became a well-known industry in the late 1970s. Then it was seen to be based on recombinant DNA technology but the word biotechnology had been coined sixty years earlier and there had been an active debate since then about how life processes could be exploited to make useful products.

Introductory article
Article Contents
. Introduction . Concept and Industry 1870 1940 . Genetic Engineering . Human Genome Programme

Introduction
Biotechnology came to the attention of policy makers as a key technology for the future at the end of the 1970s. It was a time when the rising price of oil and global competition was calling into doubt the future prosperity of traditional industries. Information technology, materials and biotechnology were widely seen as bases for future prosperity. Such was the faith in the category of biotechnology, that little regard was given to its actual meaning. The popular concept confounded two concepts: the idea of the application of biology or life processes in general, on the one hand, and, on the other, the application of specic new techniques relating to recombinant DNA and monoclonal antibodies. The confusion extended to muddle over the key products that would follow. Certainly, what made biotechnology seem a potential counterpart to information technology in a third industrial revolution were the recent advances in molecular genetics. They seemed to oer the possibilities of making industrially proteins identical to those produced in the normal human body. These might be used to compensate for single gene genetic defects aecting as many as 3% of the population while others such as interferon might be used to boost the bodys defences against such hitherto formidable foes as cancer. There was also hope that industrially useful materials such as alcohol, plastics or ready coloured bres might be made in plants, so the attractions of a potentially new agricultural regime might be as great as the implications for medicine. At a time of concern over agricultural subsidies such hopes were doubly welcome. Indeed the agricultural benets sometimes overshadowed the medical implications. However, furore over the agricultural use of genetically modied organisms meant a growing distinction between agricultural and medical aspects of biotechnology. The continuing change in the anticipated future meant that there would be continuing uncertainty as to the essential roots in the past. What they shared was a sense of the historic signicance of the changes that were already occurring. On 27 June 2000, the British Prime Minister and the American President in a linked press conference announced the completion of the draft map of the human genome. The Director of Britains Wellcome Trust was

quoted as suggesting that achievement was comparable in importance to the development of the wheel. Thereby he was integrating the event not just within the history of technology in general but also within the history of claims for biotechnology. Since the beginning of the twentieth century there had been a belief that the implications of harnessing life to technology would be momentous. Indeed the grandeur of expectations has been a dening feature of biotechnology over time. The historiography of this vision of biotechnology has often been cast as running back through the discovery of recombinant DNA techniques in 1973, the discovery of the structure of DNA in 1953, through the studies of genetics by Thomas Hunt Morgan in the 1920s to Mendels pioneering studies of the genetics of the pea in the nineteenth century. It was a solidly scientic lineage. However, biotechnology was an established industry before the impact of molecular genetics. It was associated with the most important drugs ever made, the antibiotics and hopes for world-shaking products such as starvationcuring single-cell protein, and energy-producing gasohol. The confusion between the two visions of the radically new and the well established was sometimes resolved by dierentiating between old and new biotechnology. This distinction, made by the US Oce of Technology Assessment, was too abrupt. Although it served to distinguish the potential new industry of protein manufacture from the mature if unproblematic historic microbiological industries such as brewing whose ancestry could be traced to the Babylonians, links between the twentieth century fermentation-based industries were obscured. This account suggests that rather than seeing the history of biotechnology as based on the history of genetics, it is more accurate to say that biotechnology was rescued by genetics. This account has three parts, dealing with three overlapping periods. It deals rst with the history of biotechnology as industry and as concept from its roots at the end of the nineteenth century to the impact of molecular genetics in the 1970s. Secondly it treats the quarter century from 1965 to 1990 during which the potential of molecular genetics was being negotiated. Thirdly it concludes with the human genome programme.

ENCYCLOPEDIA OF LIFE SCIENCES 2001, John Wiley & Sons, Ltd. www.els.net

History of Biotechnology

Concept and Industry 1870 1940

The so-called second industrial revolution of the period 18701914 is often associated with the development of formal research and development, and the application of science to new industries. The emergence of the chemical industry is widely taken as emblematic. Yet the development of microbiological industries might also be more frequently cited. The articulation of the germ theory by Pasteur enabled the formulation of a theory of brewing and other fermentation processes. Across Europe the implications were explored as such traditional businesses as beer, wine and cheese making were subjected to applied science. Even before the work of Pasteur the general term zymotechnology had been used to designate the variety of fermentation industries. Now it took a leap forward. In Copenhagen Emil Christian Hansen attacked the problem of erratic brewing at the Carlsberg brewery and founded the pure yeast process. His contemporary Alfred Jrgensen published a widely used textbook on zymotechnology and at his private institute of fermentology taught over seven hundred students from many countries over a period of thirty years. His pupil Orla Jensen would specialize in cheese making rather than brewing, but continued the vision of an integrated discipline. Before World War I he pioneered a course in biotechnical chemistry at Copenhagens polytechnic. Impending and then actual war accelerated the use of fermentation technologies to make strategic materials. In Britain a process to ferment butadiene for synthetic rubber production was adapted to make principally acetone as a plasticizer for explosives. This work was begun by a large consortium led by William Perkin Jr in Manchester, England, including his Manchester-based colleague Chaim Weizmann, and Auguste Fernbach at the Pasteur Institute in Paris. When Weizmann developed his own improved system, it was eagerly taken up by the British government, supplanting the product of the international collaboration. The process was technically important as the rst industrial sterile fermentation, and strategically important for munitions supplies. There is, however, no truth in the story that Lord Balfours Declaration of 1917 promising Palestine to the Jews was made in gratitude. In Germany scarce oil-based lubricants were replaced by fermentationderived glycerol developed by Wilhelm Connstein and Karl Ludecke in Berlin and animals were fed yeast grown with the aid of the new synthetic ammonia. In wartime Hungary, the problems of animal-feeding at a time when humans were crying out for scarce protein led to a search for eciency and the developing concept of the animal-machine which underpinned what the engineer Karl Ereky called biotechnology. Its use in a series of his publications from 1917 to 1919 can be considered the rst coinage of the word. Erekys concept was taken up in Germany where it was adapted to describe the use of microorganisms such as
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yeast as machines. There and elsewhere the postwar years saw many attempts to make industrial use of agricultural materials. Not only was it hoped that thereby cheaper products could be obtained, but also agricultural crisis would be stemmed. In the United States this philosophy led to the so-called Chemurgy Movement. The most widespread application was the production of ethanol fuel for internal combustion engines, from agricultural waste. More sophisticated products included the soya-beanbased plastic promoted by Henry Ford as a material for car bodies. The culmination of this tradition, which would also lay down the basis for the next generation of biotechnology, was the development of penicillin. The rst of the antibiotics was detected and named by Alexander Fleming in London in the 1920s. The technique of deep fermentation and the successful mould strain were, however, pioneered in the Northern Regional Research Laboratory in Peoria, Illinois, set up in the wake of chemurgic enthusiasm in the 1930s. Despite the belief of chemists that they would quickly synthesize the new medicine, it was produced more economically by fermenting mould in the newly developed stirred tank fermenter and by 1944 the new wonder drug was widely available, setting a new standard for medicine and a super-star success for biological technology. Such achievements as fermentation alcohol, acetone and even penicillin were accomplished by people who believed that fermentation could make a vital contribution to technological change but were not themselves philosophers. In parallel with their work, thinkers coming out of the biological community were reecting on the signicance of using living beings as machines.

Evolutionary theory: engineering heredity

From early in the twentieth century a cluster of approaches, theories and styles that could be described as neo-Lamarckian provided the context for hope and indeed expectation that the intrinsic powers of humanity could be extended and improved through scientic action. These ideas were closely linked to eugenics. While today eugenics is associated with murder, many neo-Lamarckians had hoped that humanity could be improved by positive action. A sense of impending technological revolution provided the context in which Lamarckian biological ideas about the improvement of species were transformed into conceptions about the self-improvement of mankind and new industrial modes. That translation was typically expressed through appeals to a lay audience. Three nodes in a network of thinkers and writers were particularly inuential. Many of the men I shall deal with have been forgotten and have not generally been considered part of the apostolic traditions of either biology or technology. Where they have been recalled, the links between them have been overlooked.

History of Biotechnology

The rst node includes both the Austrian experimental biologist Paul Kammerer and his friend the sociologist Rudolf Goldscheid. The second node includes the Hun , the Scottish biologist garian biologist Raoul France Patrick Geddes and his collaborator J. Arthur Thomson. As a third node I would point to men who took some of the ideas identied by those others but were far from neoLamarckian themselves: the British biologists and popularizers of science, Julian Huxley and Lancelot Hogben. Paul Kammerer would win infamy as a fraud who painted toads to make them appear as if they had changed colour. He was exposed in 1923 and subsequently shot himself. Yet he had been very popular. A Soviet lm was even made about his life. Kammerers concept of a new technology dening a new age was put at length by his close friend Rudolf Goldscheid, the Viennese Marxist feminist polymath. He was concerned with people as valuable resources. To Goldscheid it was scandalous to see the degradation and waste of lives and resources which poverty and poor conditions led to. He wished to see an upgrading of the human resource and Lamarckian biology suggested a way. He had been a leading spirit in the establishment of Austrias principal sociological society and with Kammerer he set up its social biology section. In his key work of 1911, Hoherentwicklung und Menscheno konomie, subtitled Grundlegung der Sozialbiologie, he suggested that what he called Biotechnik would be the way of the future. In almost the same words as Kammerer would use, he suggested that Biotechnik would become the dening technology of the twentieth century. It would include eugenic measures but also birth control for mothers and control of drink and poverty. Increasing quality would make up for declining quantity. Goldscheid and Kammerer had drawn upon a link between Lamarckian biology and the improvement of humankind itself. Others derived the possibility of improving biological organisms and their greater perfection compared to mere manmade crude devices. This old theme in western culture was given a name by the . During World War I Hungarian idealist Raoul France he developed his own concept of Biotechnik which he thought should dominate the development of later engineering. His work was well known in Germany with books selling in the millions. s work was hardly known in England Although France directly, within a few months of the publication of his classic work Bios in 1920, the Scottish biologist and town planner Patrick Geddes was using the word biotechnics apparently for the rst time. Geddes too sought to link life and technology. Before World War I he had characterized the technological evolution of humankind as a move from the palaeotechnic era of coal and iron to the neotechnic era , Goldscheid of chemicals, electricity and steel. Like France and Kammerer, after the war, he detected a new era based on biology, the biotechnic era. His was perhaps a more s; it included for instance practical image than France

agriculture and eugenics rather than completely new kinds of mechanics. However, for Geddes too biotechnics was part of the evolution of mankind. Through his younger friend, the writer Lewis Mumford, Geddes would have an enormous eect: Technics and Civilization, which promoted Mumfords vision of the Geddesian evolution, is itself a founding volume of the modern historiography of technology. A thrusting new English generation of experimental biologists with a special interest in genetics, including J. B. S. Haldane, Julian Huxley and Lancelot Hogben, also promoted a concept of biotechnology. Even though they had little time for formal neo-Lamarckianism, all three were on the left politically, and wanted their science of genetics to be both useful and comprehensible to the wider public. Each believed that by means of biological invention humankind could improve itself. The previous generation had already made it axiomatic that the twentieth century would be the era of the bioengineering revolution. The only question outstanding was how that would be implemented. Huxley, perhaps following Goldscheid, foresaw a combination of social and what he called biological engineering, based upon eugenics. It was this vision that underlay his claim of 1936 that: Biology is as important as the sciences of lifeless matter, and biotechnology will in the long run be more important than mechanical and chemical engineering. To the modern reader nurtured on the vision of biotechnologys prospects as predicated upon recent discoveries, this claim may seem remarkably farsighted, but even then it was already a traditional assumption. To Hogben, following Geddes, these were predominantly to be seen in the possibilities of engineering plants through breeding. He tied the progressivism of biology to the advance of socialism. Hogben and Huxley may have been erstwhile radicals but through their popular works, such as Hogbens Science for the Citizen which would become the possession of every middle-class home in Britain, they were already becoming some of the best known scientists in the land. The reaction from Julian Huxleys brother, the writer Aldous Huxley, expressed in his book Brave New World, was equally seminal as the key work of the age pouring scorn on scientism.

Bioengineering after World War II

The pragmatic and the programmatic strains of biotechnic thinking of the 1930s came together in the years after World War II. Medicine, energy and the environment were each seen to be served by a potentially powerful new technological paradigm. The manufacture of antibiotics and then steroids by means of fermentation technologies grew enormously. This provided a context for the formalizing of biotechnology as a distinct applied science. The journal Biotechnology and Bioengineering was chris3

History of Biotechnology

tened in 1961. During the 1960s food based on single-cell protein grown in fermenters on oil or glucose seemed to visionary engineers and microbiologists and to major companies to oer an immediate solution to world hunger. British Petroleum, Shell, Hoechst, Esso [Exxon], Rank Hovis McDougall and ICI as well as Japanese and Soviet enterprises made major investments. Most would lose heart as consumers rejected the idea of many of the novel foods and the price of oil rocketed in the mid-1970s. Nonetheless in the Soviet Union fermentation based protein would be a major source of animal feed through the 1980s.

which biotechnology was cast as potentially either another dreadful threat or a source of industrial redemption. The ambivalence of government-based regulators was mirrored by stock market investors alternately enthused and despondent about the prospect of specialized biotechnology companies. The phrase genetic engineering was coined in the early 1960s possibly by Arthur Tatum to reect the possible ways in which the human frame itself might be aected by molecular biology. In the 1980s and 1990s the phrase and its relative genetic modication were used to describe recombinant modication of plants and bacteria.

Genetic Engineering
Even more ambitious were the possibilities for human modication anticipated from the early 1960s. At meetings in London in 1962 and Ohio in 1963, biologists and doctors were debating the implications of human genetic engineering long before it was in practice possible. The production and administration of proteins that would compensate for the ravages of genetic disease seemed both possible and economically important. Genetic disease would, it was hoped, be controlled as bacterial disease was already being controlled by antibiotics. Biologists felt they had a responsibility to anticipate problems and to engage the public in advance of the explosion of social dynamite (to use a phrase adopted by Joshua Lederberg in a 1962 letter). During the early 1970s what had been science ction became fact, as the use of DNA synthesis, restriction enzymes and plasmids were integrated. In 1973 Stanley Cohen and Herbert Boyer successfully transferred a section of DNA from one Escherichia coli bacterium to another. At a conference in Asilomar, California, molecular biologists agreed they would hold o further work until regulations were in place to prevent danger to workers or the environment. The moratorium lasted until 1976. The debates of the mid-1970s about the future of genetic engineering were polarized between those who anticipated terrible environmental and ethical consequences and those who counterbalanced the speculative risks with equally speculative benets. The arguments were recited in a series of reports, enquiries and commissions in the USA and Europe which could be said to have themselves dened modern biotechnology. Although the products were clearly in the somewhat distant future, the issue of regulation was immediate. The need to debate a regulatory regime before enquiries, courts and parliaments tended to polarize the issues. The late 1970s were a time when environmentalists were successfully defying the nuclear industry, the rising price of oil was challenging the traditional mainsprings of industrial growth and the computer was already an icon of a new silicon-based industrial revolution. This was the context in
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A new industry
In 1979 a stock market analyst at the company E. F. Hutton applied the label biotechnology to the small group of companies anticipating a bounty from the use of genetic engineering to make therapeutic proteins. The hopes that the protein interferon made biotechnologically would cure cancer drove up stocks of biotechnology companies in the early 1980s. Other technologies sustained similar hopes. The development of monoclonal antibody technology growing out of the Nobel Prize winning work sar Milstein in Cambridge of Georges Ko hler and Ce seemed to oer new prospects for precise attacks on particular cells. This raised hopes both for commercial diagnostics and therapy. Diagnostically it has been a great success, simplifying for instance pregnancy testing. However, therapeutically its implications have been limited. Equally the administration of proteins to cure disease has proved dicult. New smaller companies were launched and increasingly oated on the New York Stock Exchange. Disappointments here and elsewhere meant that stock market movements were particularly erratic. Thus the share price of Biogen, an early biotechnology enterprise and the rst company to make interferon, was no greater in 1994 than a decade earlier, but in one quarter of 2000 had risen 2000%. Stock market interest in companies had been spurred by the 1980 decision of the US Supreme Court to permit the patenting of a new organism. Eight years earlier the Exxon researcher Ananda Chakrabarty had applied for a patent to cover an organism that metabolized hydrocarbon waste. Although it did not use genetic modication, the organisms patent seemed to open the way to future patents for engineered organisms. This patent more than any other single event signalled the commercial potential of biotechnology to governments in other countries. The early days of biotechnology were red by hopes of medical products and high value pharmaceuticals. At the same time agricultural products were also being developed. Three early products which each raised substantial problems were bacteria that inhibited the formation of frost on the leaves of strawberry plants (ice-minus

History of Biotechnology

bacteria), genetically modied plants including tomatoes and rapeseed, and the hormone bST produced in genetically modied bacteria and administered to cattle to increase milk yields. The rst to come on stream were the ice-minus bacteria. These were fought through the courts in the US through the 1980s. Although they were approved after four years of controversy they have not to date been commercialized. Genetically modied (GM) plants followed. The rst produce to enter the human food chain was chymosin, an enzyme used in the manufacture of cheese approved in 1990. The rst whole food to be approved was the FlavrSavr tomato declared to be safe in 1994. This contained antisense RNA, which expressed a protein slowing down the softening process. The Foundation for Economic Trends, headed by Jeremy Rifkin, coined the word Frankenfood to challenge the concept of GM foods in 1993. In the event the Flavr-Savr was withdrawn from the market in 1997. However, Calgene, who had manufactured it, were taken over by Monsanto, a company that would pioneer a new range of plants that were resistant to their own herbicide Round-up (such as soya beans) or contained a gene from the bacillus Bacillus thuringiensis which attacked the corn-borer beetle (e.g. corn and cotton). By 1999 half the soya beans and one-third of the corn grown in the US was modied. Whereas the use of the ice-minus products had raised most anxiety in the US, the use of these products created anxiety rst in Europe which then spread to the US. Even more controversial than the use of GM foods was the medication of cattle using the GM-derived protein, bovine somatotropin. This had been extracted from the pancreas of cattle in the 1930s and shown to increase milk production. However, the cost was disproportionately large. The advent of GM technology meant that this protein could be expressed in modied bacteria and thereby manufactured cheaply. Milk production was greatly increased, at a certain cost, some claimed, to animal health. Socioeconomic consequences were foreseen since a reduction in milk price might make smaller production units uneconomic and small farms might go out of business. In Europe the use of bST has not been approved. Such developments have been distinctively US phenomena, often associated with small companies spun-o from universities. The origins of the strong industrialacademic nexus in the US have been put down to entrepreneurial zeal. There has been a large literature on the proliferation of small companies.

the scale of the task seemed gigantic. The development of automatic sequencers in the 1980s and the prospect of an international race focused attention in the United States. Following initiatives from the Department of Energy and from the National Institutes of Health (NIH), the US government formally launched its Human Genome Project in 1990. Plans were accelerated by the threat of competition from private companies and the US government agencies were joined by Britains Wellcome Trust. When the rst draft of the entire genome was announced in May 2000 almost 68 000 pages relating to the Human Genome Project were identied by the Google browser. However, even this might grow. The potential for public anxiety about the human future was revealed as early as 1997 with the rst cloning of an adult animal, the sheep Dolly in Scotland. An intense debate emerged, much of it concerned not with the cloning of sheep which had been achieved but with the cloning of people which had not. A search with Google in July 2000 revealed almost 134 000 pages of material on the web in response to the words human and cloning, compared to 237 000 for cloning alone. When the Human Genome Project was launched it was immediately obvious that it would raise ethical, legal and social issues. The identication of genes indicating proneness to diseases for which there was no cure, such as Huntington chorea, or diseases that were inherited and therefore risk factors for an entire family could be found by one member proving positive. The Human Genome Project therefore raised possibilities that had not been encountered before. Moreover, the problems of human engineering were once more on the agenda. The problems it raised were therefore cultural as well as ethical and a large literature on the so-called Yuk Factor has explored the nature of the observable disgust that innovation has exhumed. Problems of patenting arose too. What could be patented when one is dealing with the building blocks of life? The 1986 US patent of an engineered mouse proved deeply troubling in Europe. Biotechnology is thus deeply rooted in scientic and industrial tradition. It also raises questions that are at heart old. Yet the urgency with which at the beginning of the twenty-rst century we have to make up our minds and the necessity of cultural change pushed by modern discovery, these are unprecedented.

Further Reading
Bud R (1993) The Uses of Life: A History of Biotechnology. Cambridge: Cambridge University Press. Durant J, Bauer MW and Gaskell G (eds) (1998) Biotechnology in the Public Sphere. London: Science Museum. Kenney M (1986) Biotechnology: The University Industrial Complex. New Haven, CT: Yale University Press. Kolata GB (1998) Clone: The Road to Dolly, and the Path Ahead. New York: W Morrow.

Human Genome Programme

The sequencing of the human genome and its potential modication had been discussed from the 1960s. However,

History of Biotechnology

Lederberg J (1962) Letter to Paul Doty, 15 November, National Library of Medicine. [http://www.proles.nlm.nih.gov/BB/A/H/V/N/] Pauly PJ (1996) Controlling life: Jacques Loeb and the Engineering Ideal in Biology, 2nd edn. Berkeley: University of California Press. Teitelman R (1989) Gene Dreams: Wall Street, Academia, and the Rise of Biotechnology. New York: Basic Books.

Tansey EM and Catterall PP (eds) (1995) Technology transfer in Britain: the case of monoclonal antibodies. Contemporary Record 9: 562585. Werskey G (1978) The Visible College: The Collective Biography of British Scientic Socialists of the 1930s. New York: Holt, Rinehart and Winston.