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Biotechnology can be defined as ‘applied biological science.’[3] However, the U.S. government employs a more comprehensive definition: both old and new biotechnologies comprise ‘any technique that uses living organisms (or parts of organisms) to make or modify products, to improve plants or animals, or to develop micro-organisms for specific uses.’[4] The ‘new’ biotechnology has been defined by the U.S. government as ‘the industrial use of rDNA, cell fusion, and novel bioprocessing techniques.’[5] The definition that, in the long run, may be the most descriptive, relative to the world economy, is that of Vivian Moses and corporate biotechnology pioneer, Ronald Cape: ‘making money with biology.’[6]
Biotechnology has already been employed successfully to manufacture new medicines, improve agricultural production, and produce drugs from metabolites of marine organisms and shows great promise in other areas, e.g., remediating environmental pollution. But, its most rudimentary applications are in fermentation, that is, the use of micro-organisms, such as moulds and bacteria, to produce food products. This type of application is as old as the history of human civilisation. Fermentation technology originated in ancient China, where foods were fermented by moulds, and in Egypt, where beer brewing and bread-making were combined enterprises.[7] Bread, cheese, yoghurt, vinegar, soy sauce, bean curd, beer, and wine are a few examples of the modern products of fermentation.
The unique characteristics of micro-organisms have only begun to be exploited to improve life on the planet, taking into account, of course, the role of micro-organisms in cycling of nutrients and in global climate processes. Even before the science of genetics was understood, new varieties of crops and animals were being bred by selection for desired qualities. With the advent of genetic engineering, new technologies emerge from the old.
The first industrial use of a pure culture of a bacterium was accomplished by Chaim Weizmann in 1917. Weizmann developed the fermentation of cornstarch by the bacterium, Clostridium acetobutylicum, producing acetone for explosives manufacture.
Seminal work in genetics was done in 1865 by Gregor Mendel, an Austrian monk whose studies on the pea plant elucidated inheritance of traits via hereditary factors. Although Mendel’s work was ignored until 1900, once rediscovered, his findings fitted well with what, by then, was known about chromosomal activity during cell division, or mitosis. The early to middle portion of the 20th century was an exciting time, with major gains in knowledge of genetic inheritance. Thomas Hunt Morgan of Columbia University, working with the fruit fly, Drosophila melanogaster, showed that genes, or the units of heredity, were the constructs of chromosomes. His student, A.H. Sturtevant, who later joined him when he moved to the California Institute of Technology,[8] made breakthrough discoveries, showing genes were linked, comprising chromosomes. He thus began the science of genetic mapping, a technique essential to the new genetics.
In the 1930s and 1940s, genetics research was inexorably moving in the direction of the upcoming explosion of knowledge at the molecular level. Researchers such as Barbara McClintock[9] and Marcus Rhoades[10] studied linkage and mutable characteristics in maize (corn), providing a view of genes as more mutable and variable than the simple Mendelian genetics allowed. Meanwhile, research on what comprised genetic material moved forward rapidly. In 1928, Frederick Griffith found that a ‘transforming principle’ was able to alter traits in the bacterium, Streptococcus pneumoniae.[11] By 1944, Oswald Avery, Colin MacLeod, and Maclyn McCarty of the Rockefeller Institute identified the ‘transforming factor’ as deoxyribonucleic acid, or DNA.[12] From that moment, scientists in many laboratories laboured to determine the chemical structure of the DNA molecule. Finally, in 1953, publication of James Watson’s and Francis Crick’s short paper was the breakthrough everyone was awaiting.[13]
Twenty years after Watson and Crick’s paper Stanley Cohen of Stanford University, Herbert Boyer of the University of California (San Francisco) Medical School, and their teams succeeded in cloning a gene into a bacterial plasmid, the first recombinant DNA.[14] In 1980, they received a patent for this technique, which produces recombinant or rDNA. Also in 1980, in Diamond v. Chakrabarty, the U.S. Supreme Court ruled that micro-organisms could be patented, opening a new commercial avenue for genetic engineering.[15]
The first U.S. biotechnology company, Genentech, was founded in 1976. Now, 22 years later, it is joined by more than 1300 other companies in the U.S. alone.[16] In 1981, the first U.S.-approved biotechnology product reached consumers: a monoclonal antibody-based diagnostic test kit. The following year, the first recombinant DNA pharmaceutical, Genentech’s (Eli Lilly) Humulin®, recombinant human insulin, was approved for sale in the U.S. and Great Britain. Humulin’s 1993 sales were $560 million.[17] That same year, the first recombinant animal vaccine for colibacillosis was approved in Europe. According to Lee and Burrill,[18] 1981-1987 were watershed years for U.S. bio-technology: an average of 90 companies were formed annually, making a total of 631 companies established during this period.
Although most biotechnology companies still are not consistently profitable,[19] an increasing number of products have entered the market. In 1993, Amgen’s Neupogen®, human granulocyte colony-stimulating factor, was the best-selling U.S. biotechnology drug,[20] netting $719 million.
By 1994, U.S. biotechnology companies had a market value of $41 billion, R&D expenditures of $7 billion, and 103,000 employees - this, in an industry that did not exist 20 years earlier. By comparison, the U.S. Pharmaceutical industry, which is heavily invested in biotechnology, had R&D expenditures of $13.8 billion that same year (1994).
The biotechnology industry has matured, taking on a new role in the global economy. Rather than being aggressively entrepreneurial with the intention of becoming the next Merck, the newly emerging companies serve as a reservoir for corporate research for large pharmaceutical firms, which, in turn, develop and market the output.[21] Because most of the industry is centred on health care products, and many of the companies were started on the basis of licensing agreements or research from the university community, the decrease in corporate start-ups, as well as financing, is causing a basic change in the structure of the biotechnology industry. Smaller companies have merged. Large companies, such as the major pharmaceutical companies, have acquired smaller bio-technology ventures, and, because there is little money available in the investment market for corporate growth, companies look to strategic alliances, both in the U.S. and abroad, to shore up finances and financial opportunities.[22]
The Hong Kong Institute of Biotechnology, under the auspices of the Chinese University of Hong Kong, was established with the help of overseas Chinese scientists.[23] Hong Kong also has a Biotechnology Research Institute.[24]
Within the People’s Republic of China, there are many biotechnology-related research departments and institutes, but one of the oldest and best known is the Shanghai Institute of Biochemistry.[25]
An International Vaccine Institute was established in South Korea, with financial assistance from the United Nations Development Fund and the Japanese government.[26]
Thailand’s National Centre for Genetic Engineering and Biotechnology, which has a Marine Biotechnology Laboratory, was begun with support from U.S. AID. Aquaculture is a major theme of other biotechnology research centres and university departments in Thailand.[27]
Many national and international organisations maintain laboratories worldwide that carry out research in biotechnology, for the most part related to agriculture, e.g. the International Rice Research Institute in the Philippines. The European Union, in partnership with the Queen’s University of Northern Ireland in Belfast, established a Biotechnology Centre for Animal and Plant Health, focused primarily on disease control.[28]
In the U.S. and to a lesser degree in Canada and Europe, the bulk of the biotechnology industry is focused on the biomedical field: therapeutics and diagnostics make up 68 per cent of the U.S.; 43.7 per cent of the Canadian; and approximately 43 per cent of the European industry. Therapeutic product sales in the U.S. increased 24 per cent from 1993 to 1994, to a total of nearly $20 billion.
Agricultural biotechnology also represents a growing segment of the industry: 8 per cent in the U.S.; 20 per cent in Europe; and 28 per cent in Canada. The U.S. agricultural biotechnology market showed an increase in sales of 158 per cent in the last year, with aquaculture as the most rapidly growing sector.[29]
The chemical, environmental, and services segment, which comprises only 9 per cent of the U.S. industry, increased 81 per cent in sales within the past year, totalling $70 billion.[30] It comprises 10 per cent of the Canadian industry.
Medical biotechnology includes mainly recombinant drugs and enzyme-mediated diagnostic kits, but rational design of drugs, where a drug is modelled to fit a particular molecule, yielding a limited response that can result in control of the disease process, has become a significant part of medical biotechnology. By learning more of the basic biochemistry of normal and abnormal cellular function, scientists can eventually produce drugs that will prevent abnormal growth of cancer cells, or permit detection of abnormalities in the DNA that signal the beginning of cancerous changes, thereby preventing cancer from occurring. The intent is to circumvent the immune response to one’s own tissue that occurs in auto-immune diseases, such as multiple sclerosis and lupus erythematosus. The hope, also, is to use small molecules to combat degenerative neurological diseases or to induce neurological cell regrowth in such conditions as Alzheimer’s disease, amyotrophic lateral sclerosis, head and spine injury, and cerebrovascular accident or stroke.[31] Some of the already successful recombinant drugs include recombinant human insulin, growth hormone, interferons, tissue plasminogen activator, erythropoietin and other blood cell stimulating factors. Thus, biotechnology and pharmaceutical companies legitimately have high hopes for the economic and medical potential of the next generation of drugs.
Marine biotechnology, which represents a small segment of the biotechnology industry - in the U.S. approximately 85 companies or about 7 per cent of all biotechnology companies - has applications in medicine, agriculture, materials science, natural products chemistry, and bioremediation. Most of the world’s tropical nations are very well suited to pursue marine biotechnology because of their proximity to the oceans and because of their suitable climates. Worldwide, marine aquaculture produced 14 million metric tons of fish in 199l,[32] with a market value of approximately $28 billion?[33]
Aquaculture is the branch of marine biotechnology that is most closely related to agriculture and is often included under that classification. Demand for seafood worldwide is expected to increase by 70 per cent in the next 35 years.[34] Thus, world aquaculture will need to increase production seven-fold by the year 2025 in order to meet the demand. Unfortunately, this increase in demand comes at a time when the world fisheries are over-exploited and/or ‘commercially extinct.’ [35] The USDA foresees biotechnology aiding in improvement of captive management and reproduction of species, leading to more efficient species that make better use of food supplies, production of healthier organisms, and improvement in food and nutritional qualities of the organisms. Furthermore, aquaculture can produce organisms used as biomedical models in research, reservoirs for bioactive molecule production, and organisms useful in bioremediation. Aquaculture is no longer a means of producing luxury foods, such as lobsters, but a critical solution to the world fisheries problems.
Algal aquaculture, an ancient art in Asia, not only produces seaweeds, but microalgal cultivation produces food supplements, such as the omega-3 fatty acids and beta carotene.[36] The polysaccharides of algae are a valuable commodity and a much sought after natural product.
The achievements of marine biotechnology since 1983 include many important milestones. The realisation that natural products associated with marine animals and plants are produced by bacteria is one example. It is now possible to utilise marine micro-organisms as a source of metabolites, potential antibiotics, antitumor agents, and related pharmaceuticals. There is an enormous biological diversity in the world oceans, another important discovery. The Azoic theory has been disproved, a theory which held that the deepest parts of the world oceans were devoid of life. The discovery of hydrothermal vents made it clear that there is an enormous diversity of life in the deep sea. The discoveries of large populations of viruses, of the influence of viruses in regulating algal populations, as well as of the presence of hyperthermophilic viruses in the deep sea are other examples. The numbers of viruses in estuaries have been shown to be greater than that of bacteria at certain times of the year, as well as seasonality in virus abundance and distribution.
The discovery of the Archaeae, an ancient line of micro-organisms, more closely related to higher animals and plants than to the ‘true bacteria’ has been documented and a new determination of the phylogeny of life on the planet has been derived.
Extremophiles, micro-organisms living in extreme environments such as high pH, low pH, high hydrostatic pressure, low temperature, i.e., freezing, and extremely high temperatures (above boiling), have been isolated, characterised, and shown to be a source of commercially important products.
Psychrophiles, bacteria able to grow at temperatures less than 10°C were isolated many years ago, but the potential of psychrophiles has been underestimated. It is now clear that enzymes functioning at very low temperatures have valuable commercial applications.
Novel species of marine bacteria have been isolated and described, including a giant bacterium visible to the naked eye. Also described, but not yet isolated, are bacteria occurring in abundance in deeper regions of the Sargasso Sea in the Atlantic Ocean and areas of the Pacific Ocean. These taxa cannot yet be grown in culture, but have been described by ribosomal RNA techniques.
The use of molecular probes to discover new, as yet uncultured, taxa has been widely applied and proven exciting.
It has been discovered during the past decade that pure cultures are not necessarily the best means of understanding communities of bacteria in the natural environment. In fact, mixed cultures and biofilm cultures are proving to be effective in biodegradation and in carrying out metabolic processes in the natural environment.
Successful production of effective vaccines for aquaculture, starting in the 1970s, have provided significant advances in aquaculture of a variety of marine species, including salmonids.
Application of newly developed equipment, such as laser technology, confocal microscopy, nucleic acid sequencers, and synthesisers have opened up areas in marine microbiology and allowed expansion of marine biotechnology.
Public understanding of the potential of marine biotechnology and its applications needs to be improved. For example, a fish enzyme useful in improving cheese production was not accepted because it was feared that the cheese might taste ‘fishy’. This is a misunderstanding and a strange interpretation of marine biotechnology. It would be amusing if it were not tragic in the loss to marine biotechnology.
The value of transgenic fish is not understood by the public, especially that there is a benefit in using transgenic fish for production in closed systems, especially in providing a means of obtaining fish not requiring wild stock, unlike capture fisheries.
The need to educate industry about the value of marine biotechnology is important. For example, a medium was developed containing fish peptones that was better for growing microorganisms than beef peptone-based media. However, it was difficult to break into the market because industry feared higher risks associated with utilising fish peptones, i.e., lack of a controlled source. Thus, better understanding and involvement of industry is needed.
Through application of molecular biology to the marine sciences, the potential of the oceans is opened in a way not previously anticipated or even dreamed about. Furthermore, a multi-disciplinary approach to understanding marine ecosystems will make possible cleaning up environmental pollution.
Basic research in marine molecular microbial ecology, especially of coastal areas and wetlands is needed. Community structure, eutrophication/productivity, and control of production in marine ecosystems are poorly understood. Application of marine molecular microbial ecology to bioremediation, aqua-culture, and probiotics[37] need to be developed.
Bioassays, not only against bacteria not found in the sea i.e., human pathogens, but also against bacteria naturally inhabiting the sea, such as fish pathogens, will be invaluable to better understand the interactions of bacteria. Chemical signalling pheromones and other bioactive products regulating growth (initiation, cessation, maintenance in micro-organisms, as well as signalling between organisms), will be very useful in research and in industry.
New efforts are required for isolating and culturing what are now non-culturable bacteria, as well as improved methods for isolating marine bacteria that are culturable, but for which media are not yet available. There is no operating collection for marine micro-organisms. The Torrey Research Station in Aberdeen, Scotland no longer maintains a culture collection for marine micro-organisms.
Microbial adhesion needs to be better understood, especially in relation to antifouling. A rational system for understanding attachment and the fouling process, in general, needs to be developed. It is not understood whether adhesion in the marine environment is different from that in the terrestrial environment. Research needs to be done to answer this question. Biomaterials research needs to be undertaken. For example, marine organisms form very strong, flat, hard structures in aquatic systems, and they attach to both hard and soft surfaces. Understanding this kind of attachment would have application in medicine, aqua-culture, and in material sciences, (paints and painted surfaces).
The eggs of fish, from larvae to adults, offer a model for understanding biological development and evolution. Germ-free fish research laboratory facilities would be very helpful in understanding the role of bacteria in providing nutrients for invertebrate growth and development.
Host parasite and host pathogen interactions in the marine environment will allow better understanding of the disease process and especially the gradation from mutualism to commensalism to symbiosis to pathogenesis to parasitism.
Gene transfer takes place in the environment and levels of gene expression need to be better understood. Marine microbial genetics and distribution of genetic systems in the ocean are very important. In fact, the behaviour of fish in schools and fluctuating productivity occurring in areas where aquaculture is practised, much like the phenomenon of farmed soil becoming ‘tired,’ suggests that microbial replenishment and productivity fluctuation can be analysed.
Onset and termination of algal blooms and management of the oceans would be possible by understanding basic genetics.
Organisms found in the sea offer a new perspective on microbial capacity to colonise even the most extreme niches. New physiological understanding of micro-organisms can be provided therefrom.
cDNA sequencing would be invaluable. Surveys and sampling of EST fragments would allow better understanding of phylogenetic diversity in the oceans.
Some reactions occur only in undisturbed consortia. Industry demands to know how natural consortia work and at what rates. Therefore, using micro-organisms to clean polluted sites, such as polluted bays and estuaries is a high priority. Many chlorinated compounds are found in the ocean. There are active dechlorinating bacteria in the sea, which could be utilised for detoxifying purposes.
The immediate, significant benefits of marine biotechnology lie in the new discoveries of unusual forms of life. New antibiotics and antitumor agents can be obtained from the sea. Unique chemicals exist in the sea that are synthesised by marine bacteria and for which there may be industrial applications. Furthermore, the discovery of the abundance of viruses in the sea makes it highly likely that genetic transformations occur in the oceans, i.e., gene transfer, which is less known in the marine environment and, therefore, can provide information on the origin of viruses.
Bringing young scientists into working collaborations and making known the possibilities of marine molecular biology to scientists is important. It is an underdeveloped area of great promise.
It is critical also to educate the public and overcome ignorance of the potential of the marine biotechnology contributions to society. Risk studies need to be done to alleviate the fear of use of transgenic fish as food and to replenish exhausted fisheries of the world nations.
There seems to be a lack of understanding of marine environments and marine systems by industry. Industry almost seems to ‘go out of its way’ to avoid the marine environment. Marine fermentations do not rust out equipment if proper materials are used and a careful approach is taken.
The oceans represent the last great frontier for discovery of new materials, medicines, and foods.
Marine biotechnology has numerous applications in areas other than those related to food production.[38]
Marine natural products have application in fields as far ranging as molecular biology and bioremediation, to adhesives and pharmaceuticals. Enzymes isolated from thermophilic Archaea, micro-organisms originally thought to be bacteria, some of which live in deep sea hydrothermal vents, are essential to molecular geneticists doing DNA sequencing. Agar, an important ingredient in nutrient substrates for
growth of micro-organisms in culture, and agarose, used for making gels for biochemical genetics and protein studies, are derived from algae.
The marine bacterium Acinetobacter calcoaceticus RAG-1, emulsifies hydrocarbons. Metal-concentrating marine bacteria have also been identified and may prove useful in marine bioremediation.
The strength of adhesives produced by marine organisms, such as mussels and barnacles, has been recognised and, with the advent of modem biomolecular techniques, scientists have been able to study and duplicate some of these materials.
Some of the most potent natural toxins known to science are produced by marine organisms. These toxins may be used in research applications, such as studies of the neuromuscular junction, where much of their toxic activity is concentrated. They also may yield potent anti-neoplastic drugs.
Monitoring of the marine environment may give us clues about environmental degradation and studies of marine ecology, including the problem of pollution of shorelines by bacterial pathogens, will provide improved human health.
Basic science is needed in marine biotechnology, molecular marine biology, and biotechnology generally. Engineering doesn’t ‘happen’ unless the basic science framework is in place. Centres might be established, much like the Science and Technology Centers and the Engineering Research Centers of the NSF/U.S. These would be excellent opportunities to recognise existing strengths, e.g., aquaria, ship facilities, marine laboratories. Multidisciplinary workshops can be highly beneficial by linking several labs that are attacking the same problem.
To fulfil the promise of marine biotechnology, there is still a great deal of research that needs to be done to understand the structure of marine communities and their dynamics in responding to usual environmental variations and, especially, to anthropogenic stresses. Not only is molecular marine biology important for such applications in marine biotechnology, but it is also critical for understanding biodiversity and marine ecology, as new applications for marine products and processes are developed.
[1] University of Maryland Biotechnology Institute, Center of Marine Biotechnology, Baltimore, MD 21202.
[2] Paper prepared for International Symposium on Progress and Prospect of the Marine Biotechnology (ISPPMB’98), October 6-10, 1998, Qingdao, P. R. China
[3] Webster’s Ninth New Collegiate Dictionary, Springfield, MA, Merriam-Webster Inc., 1984.
[4] Congress of the United States, Office of Technology Assessment, Commercial biotechnology: an international analysis, 1984, 612 pp. Available from U.S. Government Printing Office, Washington, DC, OTA-BA-218.
[5] Congress of the United States, Office of Technology Assessment, Biotechnology in a global economy, 1991, 292 pp. Available from U.S. Government Printing Office, Washington, DC, S/N 052-003-01258-8.
[6] Vivian Moses, and Ronald E. Cape, (eds) Biotechnology: The Science and the Business, New York, Harwood Academic Publishers, 1991.
[7] M.J.R. Nout, ‘Upgrading traditional biotechnological processes’ in Applications of Biotechnology to Traditional Fermented Foods, Report of an Ad Hoc Panel of the Board on Science and Technology for International Development, Office of International Affairs, National Research Council, Washington, DC, National Academy Press, 1991, pp. 11-19.
[8] Lily E. Kay, The Molecular Vision of Life, Caltech, The Rockefeller Foundation, and the Rise of the New Biology, New York, Oxford University Press, 1993.
[9] Barbara McClintock, ‘A 2n-1 chromosomal chimera in maize’, J Heredity 1929, vol. 20, p. 218.
[10] M. M. Rhoades, ‘The genetic control of mutability in maize’, Cold Spring Harbor Symp. Quantitative Biol., 194 1, vol. IX, pp. 138-144.
[11] F. Griffith, ‘The significance of pneumococcal types’, J. Hygiene, 1928, vol. 27, pp. 113-159.
[12] O.T. Avery, C. M. MacLeod and M. McCarty, ‘Studies on the chemical nature of the substance inducing transformation of pneumococcal types. Induction of transformation by a deoxyribonucleic acid fraction isolated from pneumococcus type III’, J. Exp. Med., 1944, vol. 79, pp. 137-158.
[13] J.D. Watson and F. H. C. Crick, ‘Molecular structure of nucleic acids’, Nature, 1953, vol. 171, pp. 740-741.
[14] Stanley N. Cohen, Annie C.Y. Chang, Herbert W. Boyer and Robert Helling, ‘Construction of biologically functional bacterial plasmids in vitro’, Proc. Natl. Acad. Sci. USA, 1973, vol. 70, pp. 3240-3244.
[15] Congress of the United States, Office of Technology Assessment, 1991, op. cit.
[16] Kenneth B. Lee Jr. and G. Steven Burrill, Biotech 95: Reform, Restructure, Renewal, Ernst & Young LLP, CA, Palo Alto, 1994. ibid.
[17] ibid.
[18] ibid.
[19] Congress of the United States, Office of Technology Assessment, 1991, op. cit.
[20] Lee and Burrill, ibid.
[21] Jules Musing, talk given at New York Biotechnology Association, Annual Meeting, New York, NY, Sept. 21,1994.
[22] KPMG Health Care and Life Sciences Practice, Biopartnering Review: A Global Perspective on the Deals that Drive the Industry, 1994.
[23] M.E. Watanabe, ‘Hong Kong expands its biotech effort despite eventual Chinese takeover’, Genetic Engineering News, 1990, vol. 10, no. 2, p. 23.
[24] KPMG, Biotech Industry Briefing, 1993.
[25] Dean H. Hamer and Shain-dow Kung, Biotechnology in China, Washington, DC, National Academy Press, 1989.
[26] Jon Cohen, ‘Bumps on the vaccine road’, Science, 1994, vol. 265, pp. 1371-1373.
[27] KPMG, ibid., 1993.
[28] Anon, ‘New UK biotech center’, Biotechnology Notes, 1994, vol. 7, no. 10, p. 5.
[29] Marine biotechnology and aquaculture. USDA. Draft report dated 2/7/94, cited in Lee and Burrill, op. cit.
[30] Lee and Burrill, op. cit.
[31] Lee and Burrill, op. cit..
[32] Raymond A. Zilinskas, Rita R. Colwell, Douglas W. Lipton and Russell Hill, A Draft Report on the Global Challenge of Marine Biotechnology: A Status Report on Marine Biotechnology in the United States, Japan and Other Countries, The National Sea Grant College Program and Maryland Sea Grant College, College Park, MD, 1994.
[33] FAO, Aquaculture Production 1985-1991, Fisheries Circular #815, Rev. 5, FAO, Rome, June, 1993.
[34] U.S. Department of Agriculture, Draft of the Marine Biotechnology and Aquaculture Report, Feb. 1994.
[35] Tony Emerson, ‘It’s over for fishing here’, Newsweek, April 25, 1994, pp. 31-35; Anne Swardson, ‘Net loss: fishing decimating oceans’ unlimited bounty’ The Washington Post, August 14, 1994, p. A28.
[36] Zilinskas et al., op. cit.
[37] i.e. treatment by the ingestion of bacteria that support the useful and harmless bacteria in the body against the harmful ones. [Ed. note.]
[38] Zilinskas et al., op. cit.
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