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Chapter 5
The Chemical Industry
Chapter 5
PageBackground . . . . . . . . . . . . . . . . . . . . . . . . . 85Overview of the Industry . . . . . . . . . . . . . . . . . . 85
Fermentation and the Chemical Industry. . . . . 87New Process Introduction. . . . . . . . . . . . , , . . . . 89
Characteristics of Biological ProductionTechnologies. . . . . . . . . . . . . . . . . . . . . . . . . 90Renewable Resources. . . . . . . . . . . . . . . . . . 90Physically Milder Conditions. . . . . . . . . . . . . 91One-Step Production Methods. . . . . . . . . . . . 91Reduced Pollution... . . . . . . . . . . . . . . . . . 91
Industrial Chemicals That May Be Produced byBiological Technologies. . . . . . . . . . . . . . . . . 92
Fertilizers, Polymers, and Pesticides. . . . . . . . . 94Constraints on Biological Production Techniques 96An Overview of Impacts . . . . . . . . . . . . . . . . . . . 97
Impacts on Other Industries. . . . . . . . . . . . . . . 97Impacts on University Research. . . . . . . . . . . . 98The Social Impacts of Local Industrial Activity . 99Impacts on Manpower. . . . . . . , . . . . . . . . . . . 99
Tables
Table No. Page9. Data for Commercially Produced Amino
Acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
10.
11.12.
13.
14.
15.
16.
17.18.19.
Summary of Recent Estimates of PrimaryU.S. Cost Factors in the Production of Lysine Monohydrochloride by Fermentationand Chemical Synthesis. . . . . . . . . . . .Some Commercial Enzymes and Their UExpansion of Fermentation Into theChemical Industry, . . . . . . . . . . . . . . .The Potential of Some Major PolymericMaterials for Production Using Biotechnology 95Some Private Companies WithBiotechnology Programs ., . . . . . . . . . . . . , . 98Distribution of Applied Genetics Activityin Industry . . . . . . . . . . . . . . . , . . . . . . . . . . 100Manpower Distribution of a Firm WithApplied Genetics Activity. . . . . . . . . . . . . . . . 100Index to Fermentation Companies. . . . . . . . . 100Fermentation Products and Producers . . . . . 101U.S. Fermentation Companies . . . . . . . . . . . . 103
Figures
Figure No. Page24. Flow of industrial Organic Chemicals From
Raw Materials to Consumption . . . . . . . . . . . 8625. Diagram of Alternative Routes to Organic
Chemicals , . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Chapter 5
The Chemical Industry
BackgroundThe organic substances first used by humans
to make useful materials such as cotton, linen,silk, leather, adhesives, and dyes were obtainedfrom plants and animals and are natural and re-newable resources. In the late 19th century,coal tar, a nonrenewable substance, was foundto be an excellent raw material for many organ-ic compounds, When organic chemistry devel-oped as a science, chemical technology im-proved. At about the same time relatively cheappetroleum became widely available. The indus-try shifted rapidly to using petroleum as its ma-jor raw material.
The chemical industry’s constant search forcheap and plentiful raw materials is now aboutto come full circle. The supply of petroleum,which presently serves more than 90 percent ofthe industry’s needs, is severely threatened byboth dwindling resources and increased costs. Ithas been estimated that at the current rate ofconsumption, the world’s petroleum supplieswill be depleted in the middle of the next cen-tury. Most chemical industry analysts, there-fore, foresee a shift first back to coal and then,once again, to the natural renewable resourcesreferred to as biomass. The shifts will notnecessarily occur sequentially for the entire
Overview of the industryThe chemical industry is one of the largest
and most important in the world today. The U.S.market for synthetic organic chemicals alone,excluding primary products made from petro-leum, natural gas, and coal tar, exceeded $35billion in 1978.
The industry’s basic function is to transformlow-cost raw materials into end-use products ofgreater value. The most important raw materi-als are petroleum, coal, minerals (phosphate,carbonate), and air (oxygen, nitrogen). Roughlytwo-thirds of the industry is devoted to produc-
chemical industry. Rather, both coal and bio-mass will be examined for their potential roleson a product-by-product basis. 1
The chemical industry is familiar with thetechnology of converting coal to organic chem-icals, and a readily available supply exists. Coal-based technologies will be used to produce awide array of organic chemicals in the near fu-ture. * Nevertheless, economic, environmental,and technical factors will increase the industry’sinterest in biomass as an alternative source forraw materials. Applied genetics will probablyplay a major role in enhancing the possibilitiesby allowing biomass and carbohydrates fromnatural sources to be converted into variouschemicals. Biology will thereby take on the dualrole of providing both raw materials and a proc-ess for production.
‘For further details see Ener,qv From Biologica/ Processes, ~wl. 1,OTA.E-124 (Washington, D. C.: office of ‘rechnolo~v Assessment,July 1980).
*Most important organic intermediiites (chemical compoundsused fol. the illdustl’iitl s.vnthesis of c~n~n]et.ciiil produ(’ts SU(’11 iispliist i(:s itnd fihers) can be obtained from coal as an iilterniit i\(l Iiiiinliiteriiil. (kirrentl. v, methods iire heing dtn’elopecl to (’onirrt {’oiilinto “s.vnthetic gas, ” which (;i]n then h{’ used ils ]’ii}~ l]]i~t[>}”ii]l fo].turther conivwions.
ing inorganic chemicals such as lime, salt, am-monia, carbon dioxide, chlorine gas, and hydro-chloric and other acids.
The other third, which is the target for bio-technology, produces organic chemicals. Its out-put includes plastics, synthetic fibers, organicsolvents, and synthetic rubber. (See figure 24.)In general, petroleum and natural gas are firstconverted into “primary products” or basic or-ganic chemicals such as the hydrocarbons ethyl-ene and benzene. These are then converted intoa wide range of industrial chemicals. Ethylene
85
76-565 0 - 81 - 7
86 . Impacts of Applied Genetics —Micro-Organisms, Plants, and Animals
Figure 24.-Flow of Industrial Organic Chemicals From Raw Materials to Consumption
Organic resources
80% raw material from petroleum/natural gas
20°/0 raw material from coal, coke, andrenewable resources
SOURCE: U.S. Industrh?l Outlook (W.shlngton, D. C.: Department of Commerce, 1978); Kline Gu/de to Chemioel Industry, Fairfield,N.J., adapted from Tong, 1979.
Ch. 5—The Chemical industry ● 87
alone serves as the basic chemical for the manu-facture of half of the largest volume industrialchemicals. Each of the steps in a chemical con-version process is controlled by a separate reac-tion, which is often performed by a separatecompany.
Evaluating the competitiveness both of aprocess and of the market is critical for thechemical industry, which is intensive for cap-ital, energy, and raw materials. Its plants uselarge amounts of energy and can cost hundredsof millions of dollars to build, and raw materialcosts are generally 50 to 80 percent of a prod-uct’s cost. If a biological process can use thesame raw materials and reduce the process costby even 20 percent, or allow the use of inexpen-sive raw materials, it could provide the industrywith a major price break.
Fermentation andthe chemical industry
The production of industrial chemicals byfermentation is not new. Scores of chemicalshave been produced by micro-organisms in thepast, only to be replaced by chemical produc-tion based on petroleum. In 1946, for example,27 percent of the ethyl alcohol in the UnitedStates was produced from grain and grain prod-ucts, 27 percent from molasses, a few percenteach from such materials such as potatoes, pine-apple juice, cellulose pulp, and whey, and only36 percent from petroleum. Ten years lateralmost 60 percent was derived from petroleum.
Even more dramatically, fumaric acid was atone time produced on a commercial scalethrough fermentation, but its biological produc-tion was stopped when a more economical syn-thesis from benzene was developed. Frequently,after a fermentation product was discovered,alternative chemical synthetic methods weresoon developed that used inexpensive petro-leum as the raw material.
Nevertheless, for the few chemical entitiesstill produced by fermentation, applied genetics
has contributed to the economic viability of theprocess. The production of citric and lacticacids and various amino acids are among theprocesses that have benefited from genetics.Lactic acid is produced both synthetically andby fermentation. Over the past 10 to 20 years,manufacture by fermentation has experiencedcompetition from chemical processes.
The organisms used for the production of lac-tic acid are various species of the bacterium Lac-tobacillus. Starting materials may be glucose, su-crose, or lactose (whey). The fermentation perse is efficient, resulting in 90 percent yields, de-pending on the original carbohydrate. Sincemost of the problems in the manufacture of lac-tic acid lie in the recovery procedure and not infermentation, few attempts have been made toimprove the industrial processes throughgenetics.
Citric acid is the most important acidulant,and historically has held over 55 to 65 percentof the acidulant market for foods. * It is alsoused in pharmaceuticals and miscellaneous in-dustrial applications. It is produced commercial-ly by the mold Aspergillus niger. Surprisingly lit-tle work has been published on improving citricacid-producing strains of this micro-organism.Weight yields of 110 percent have recently beenreported in A. niger mutants obtained by ir-radiating a strain for which a maximum yield of29 percent had been reported.
Amino acids are the building blocks of pro-teins. Twenty of them are incorporated intoproteins manufactured in cells, others servespecialized structural roles, are important meta-bolic intermediates, or are hormones and neu-rotransmitters. All of the amino acids are usedin research and in nutritional preparations,with most being used in the preparation ofpharmaceuticals. Three are used in large quan-tities for two purposes: glutamic acid to manu-facture monosodium glutamate, which is a fla-
● The other two important acidukmts, or acidifying agents, arephosphoric acid (20 to 25 percent) and maltc acid (S percent),
88 . Impacts of Applied Genetics—Micro-Organisms, Plants, and Animals
vor enhancer particularly in oriental cooking;*and lysine and methionine as animal feed ad-ditives.
Conventional technology for producing glu-tamic acid is based on pioneering work that wassubsequently applied to other amino acids. Theproduction employed microbial strains to pro-duce amino acids that are not within their nor-mal biosynthetic capabilities. This was accom-
“Monosodium glutamate is the sodium salt of glutamic acid. In1978, about 18,000 tonnes were manufactured in the UnitedStates and about 11,000 tonnes imported. The food industry con-sumed 97 percent. The fermentation plant of the Stauffer Chem-ical Co. in San Jose, Calif., is the sole U.S. producer. The microbesused in glutamic acid fermentation (Corynebacferium glutamicum,
C. Iileum, and Brevibacterium j?avum) produce it in 60 percent oftheoretical yield. Thus, there is some but not great potential forthe use of applied genetics to improve the yield. Many of the ge-netic approaches have already been thoroughly investigated by in-dustrial scientists.
plished by using two methods: I) manipulatingmicrobial growth conditions, and 2) isolatingnat urally occurring mutants.
Although microbial production of all theamino acids has been studied, glutamic acid andL-lysine* * are the ones produced in significantquantities by fermentation processes. (See table9.) The production of L-lysine is an excellent ex-
“ *The lack of a single amino acid can retard protein synthesis,and therefore growth, in a mammal. The limiting amino acid is afunction of the animal and its feed. The major source of animalfeed in the United States is soybean meal. The limiting amino acidfor feeding swine is lysine, the limiting amino acid for feedingpoultry is methionine. Because of increased poultry demand,world demand for Iysine is climbing, Eurolysine is spending $27million to double its production capacity in Amiens, France, to 10thousand tonnes. The Asian and Mideast markets are ;stimated toincrease to 3 thousand tonnes in 1985. Some bar .eria producelysine at over 90 percent of theoretical yield, L:[tle genetic im-provement is likely in this conversion yield, however, significantimprovement can be made in the rate and final concentration.
Table 9.—Data for Commercially Produced Amino Acidsa
Price March Potential for application of1980 (per kg Production 1978 biotechnology (de novo synthesis or
Amino acid pure L) Present source (tonnes) bioconversion; organisms and enzymes)Alanine. ... .. ... ... ... ... .$ 80
Arginine . . . . . . . . . . . . . . . . . . .Asparagine. . . . . . . . . . . . . . . . .Aspartic acid . . . . . . . . . . . . . . .
Citrulline. . . . . . . . . . . . . . . . . . .Cysteine. . . . . . . . . . . . . . . . . . .Cystine. . . . . . . . . . . . . . . . . . . .DOPA (dihydrophenylalanine) .Glutamic. . . . . . . . . . . . . . . . . . .Glutamine. . . . . . . . . . . . . . . . . .Histidine. . . . . . . . . . . . . . . . . . .Hydroxyproline . . . . . . . . . . . . .Isoleucine. . . . . . . . . . . . . . . . . .Leucine. . . . . . . . . . . . . . . . . . . .Lysine. . . . . . . . . . . . . . . . . . . . .
Methionine. . . . . . . . . . . . . . . . .
Ornithine . . . . . . . . . . . . . . . . . .Phenylalanine . . . . . . . . . . . . . .
Proline . . . . . . . . . . . . . . . . . . . .Serine. . . . . . . . . . . . . . . . . . . . .Threonine. . . . . . . . . . . . . . . . . .Tryptophan. . . . . . . . . . . . . . . . .Tyrosine. . . . . . . . . . . . . . . . . . .Valine . . . . . . . . . . . . . . . . . . . . .
285012
2505060
7504
55160280350
55350
265
6055
125320150110
1360
Hydrolysis of protein; 10-50(J) b –chemical synthesis
Gelatin hydrolysis 200-300 (J) Fermentation in JapanExtraction 10- 50(J) –Bioconversion offumaric acid 500-1,000 (J) Bioconversion
10-90 (J) Fermentation in JapanExtract ion 100- 200(J) –Extraction 100- 200(J) –Chemical 100- 200(J) —Fermentation 10,000-100,000 (J) De novo: Micrococcus gutamicusExtraction 200-300 (J) Fermentation in Japan— 100-200 Fermentation in JapanExtraction from collagen 10-50 —Extraction—Fermentation (800A)Chemical (20%)
Chemical from acrolein
—Chemical from
benzaldehydeHydrolysis of gelatin——Chemical from indoleExtraction—
aproduction data largely from Japan because of relative Small U.S. production.L
10-50 (J)50-100(J) Fermentation in Japan10,000 (J) (80% by fermentation) De novo:
Corynebacterium glutamicum andBrevibacterium flavum
17,000(D,L) c —20,000 (D,L) (J)10-50 (J) Fermentation in Japan50-100 (J) Fermentation in Japan
10-50 (J) Fermentation in Japan10-50 (J) Bioconversion in Japan50-10 (J) Fermentation in Japan55 (J)50- 100(J) -50-100 (J) Fermentation in Japan
‘Japan.CD and L forms.
SOURCE: Massachusetts Institute of Technology.
Ch. 5—The Chemical Industry . 89
ample of the competition between chemical and mostly from Japan and South Korea. Recentbiotechnological methods. Fermentation has estimates of primary U.S. cost factors in thebeen gradually replacing its production by competing production methods are summarizedchemical synthesis; in 1980, 80 percent of its in table 10. Fermentation costs are lower for allworldwide production is expected to be by mi- three components of direct operating costs:crobes. It is not produced in the United States, labor, material, and utilities.which imported about 7,000 tonnes in 1979,
Table 10.—Summary of Recent Estimates of Primary U.S. Cost Factors in the Production ofL= Lysine Monohydrochloride by Fermentation and Chemical Synthesis
Cost factors in Production of 98% L-lysine monohvdrochloride
By fermentation By chemical synthesis
Requirement Estimated 1976 cost Requirement Estimated 1976 cost(units per unit per unit product (units per unit per unit product
(product) Cents/lb Cents/kg product) Cents/lb Cents/lbTotal Iaborc. . . . . . . . . . . . . . . . . — 8 18 — 9 20Materials
Molasses . . . . . . . . . . . . . . . . 44 7 16 —Soy beanmeal, hydrolyzed. . .
— —0.462 4 9 —
Cyclohexanol. . . . . . . . . . . . . —— —
— 0.595 17 37Anhydrous ammonia. . . . . . . — — — 0.645 6 14Other chemicalsd. . . . . . . . . . — 7 15 — 4 10Nutrients and solvents. . . . . — — — — 4 8Packaging, operating, and
maintenance materials. . . 10 22 — 9 21Total materials. . . . . . . . . . — 28 62 — 45 90
Total utilities . . . . . . . . . . . . . . — 6 12 — 7 16Total direct operating cost — 42 92 — 56 126Plant overhead, taxes,
and insurance . . . . . . . . — 10 21 — 10 21
Total cash cost . . . . . . . . . — 52 11 — 66 147Depreciation. . . . . . . . . . . — 16 35 — 13 28Interest on working capital — 1 3 — 1 3
Total costg . . . . . . . . . . . — 69 151 — 80 178
aAggumes a 23-percent yield on molasses.bAssumes a 65-percent yield on cyclohexanol.clncludes operating, maintenance, and control laboratory labor.dFor both the proce~~ of fermentation and chemical synthesis, assumed use of hydrochloric acid (~ percent) and ammonia (n percent). For fermentation includes dSO
potassium diphosphate, urea, ammonium suifate, calcium carbonate, and magnesium sulfate. For chemical synthesis also includes nitrosyl chloride, sulfuric acid,and a credit for ammonium sulfate byproduct.
~otal utiiities for both processes include cooling water, steam process water, and electricity. For chemical synthesia, natural gas is also included.fTen percent ~r year of fixed capital costs for a new 20 million lb per year U.S. plant built in 1975 at assumed capital cost of $36.6X 10’ for fOrmOntatiOn and $32.5x 10’
for chemical synthesis exclusive of land costs.
SOURCE: Stanford Research Institute, Chemical Economics Handbook 563:3401, May 1979.
New process introductionThe development of biotechnology should be
viewed not so much as the creation of a new in-dustry as the revitalization of an old one. Bothfermentation and enzyme technologies willhave an impact on chemical process develop-ment. The first will affect the transition fromnonrenewable to renewable raw materials. The
second will allow fermentation-derived prod-ucts to enter the chemical conversion chains,and will compete directly with traditional chem-ical transformations. (See figure 25. ) Fermenta-tion, by replacing various production steps,could act as a complementary technology in theoverall manufacture of a chemical.
90 ● Impacts of Applied Genetics-Micro-Organisms, Plants,and Animals
Figure 25.—Diagram of Alternative Routes to Organic Chemicals
Petroleum Carbohydrates
% followed by number indicatea iength of carbon chain.SOURCE: (3. E. Tong, “industrial Chemicals From Fermentation Enzymes,” M/croLr. TechrroL, voi. 1,1979, PP. 173-179.
Characteristics of biologicalproduction technologies
The major advantages of using commercialfermentation include the use of renewable re-sources, the need for less extreme conditionsduring conversion, the use of one-step produc-tion processes, and a reduction in pollution. Amicro-organism might be constructed, for ex-ample, to transform the cellulose in wood di-rectly into ethanol. * (App. 1-D, a case study ofthe impact of genetics on ethanol production,elaborates these points. )
RENEWABLE RESOURCESGreen plants use the energy captured from
sunlight to transform carbon dioxide from the“If IWILI(WI I“OIS iil)~)]S()\’i~l 01 SU(SI1 illl it(s(:oilll)lislllllel~l I)$v I’DNA
Icchniqut?s wits sulmlilted to lht> Ik:otl]l)iiliii)l DNA A d v i s o r y(kmlnlilltw ill the %?pl. 25, 1980 mt?eling.
atmosphere into carbohydrates, some of whichare used for their own energy needs. The restare accumulated in starches, cellulose, lignins,and other materials called the biomass, which isthe foundation of all renewable resources.
The technologies of genetic engineering couldhelp ease the chemical industry’s dependenceon petroleum-based products by making the useof renewable resources attractive. All micro-organisms can metabolize carbohydrates andconvert them to various end products. Exten-sive research and development (R&D) hasalready been conducted on the possibility ofusing genetically engineered strains to convertcellulose, the major carbohydrate in plants, tocommercial products. The basic building blockof cellulose—glucose—can be readily used as araw material for fermentation.
Ch. 5—The Chemical industry ● 91
other plant carbohydrates include corn-starch, molasses, and lignin. The last, a polymerfound in wood, could be used as a precursor forthe biosynthesis of aromatic (benzene-like)chemicals, making their production simpler andmore economical. Nevertheless, the increase inthe price of petroleum is not a sufficient reasonfor switching raw materials, since the cost ofcarbohydrates and other biological materialshas been increasing at a relative rate.
PHYSICALLY MILDER CONDITIONSIn general, there are two main ways to speed
chemical reactions: by increasing the reactiontemperature and by adding a catalyst. A catalyst(usually a metal or metal complex) causes onespecific reaction to occur at a faster rate thanothers in a chemical mixture by providing a sur-face on which that reaction can be promoted.Even using the most effective catalyst, the con-ditions needed to accelerate industrial organicreactions often require extremely high tem-peratures and pressures—several hundred de-grees Celsius and several hundred pounds persquare inch.
Biological catalysts, or enzymes, on the otherhand can speed-up reactions without the needfor such extreme conditions. Reactions occur indilute, aqueous solutions at the moderate condi-tions of temperature, pressure, and pH (a meas-ure of the acidity or alkalinity of a solution) thatare compatible with life.
ONE-STEP PRODUCTION METHODSIn the chemical synthesis of compounds, each
reaction must take place separately. Becausemost chemical reactions do not yield pure prod-ucts, the product of each individual reactionmust be purified before it can be used in thenext step. This approach is time-consuming andexpensive. If, for example, a synthetic schemethat starts with ethylene (a petroleum-basedproduct) requires 10 steps, with each step yield-ing 90 percent product (very optimistic yields inchemical syntheses), only about one-third of theethylene is converted into the final end product.Purification may be costly; often, the chemicalsinvolved (such as organic solvents for extrac-tions) and the byproducts of the reaction aretoxic and require special disposal.
In biological systems, micro-organisms oftencomplete entire synthetic schemes. The conver-sion takes place essentially in a single step,although several might occur within the orga-nisms, whose enzymes can transform the pre-cursor through the intermediates to the desiredend product. Purification is not necessary.
REDUCED POLLUTIONMetal catalysts are often nonspecific in their
action; while they may promote certain reac-tions, their actions are not ordinarily limited tomaking only the desired products. Consequent-ly, they have several undesirable features: theformation of side-products or byproducts; theincomplete conversion of the starting materi-al(s); and the mechanical and accidental loss ofthe product.
The last problem occurs with all types of syn-thesis. The first two represent inefficiencies inthe use of the raw materials. These necessitatethe separation and recycling of the side-prod-ucts formed, which can be difficult and costlybecause they are often chemically and physi-cally similar to the desired end products. (Mostseparation techniques are based on differencesin physical properties—e.g., density, volatility,and size.)
When byproducts and side-products have novalue, or when unconverted raw material can-not be recycled economically, problems ofwaste disposal and pollution arise. Their solu-tion requires ingenuity, vigilance, energy, anddollars. Many present chemical processes createuseless wastes that require elaborate degrada-tion procedures to make them environmentallyacceptable. In 1980, the chemical industry is ex-pected to spend $883 million on capital outlaysfor pollution control, and well over $200 millionon R&D for new control techniques and re-placement products. These figures do not in-clude the millions of dollars that have beenspent in recent years to clean up toxic chemicaldumps and to compensate those harmed bypoorly disposed wastes, nor do they include thecost of energy and labor required to operatepollution-control systems.
A genetically engineered organism, on theother hand, is designed to be precursor- and
92 . Impacts of Applied Genetics— Micro-Organisms, Plants, and Animals
product-specific, with each enzyme havingessentially 100-percent conversion efficiency.An enzymatic process that carries out the sametransformation as a chemical synthesis pro-duces no side-products (because of an enzyme’shigh specificity to its substrate) or byproducts(because of an enzyme’s strong catalytic power).Consequently, biological processes eliminatemany conventional waste and disposal problemsat the front end of the system-in the fer-menter. This high conversion efficiency reducesthe costs of recycling. In addition, the efficiencyof the biological conversion process generallysimplifies product recovery, reducing capitaland operating costs. Furthermore, by theirnature, biologically based chemical processes,tend to create some waste products that are bio-degradable and valuable as sources of nutrients.
Specific comparisons of the environmentalhazards produced by conventional and biologi-cal systems are difficult. Data detailing thepollution parameters for various current chem-ical processes exist, but much less informationis available for fermentation processes, and few
Industrial chemicals thatby biological technologies
Despite the benefits of producing industrialchemicals biologically, thus far major fermenta-tion processes have been developed primarilyfor a few complex compounds such as enzymes.(See table 11.) Biological methods have also beendeveloped for a few of the simpler commoditychemicals: ethanol, butanol, acetone, aceticacid, isopropanol, glycerol, lactic acid, and citricacid.
Two questions are critical to assessing thefeasibility or desirability of producing variouschemicals biologically:
I. Which compounds can be produced bio-logically (at least theoretically)?
2. Which compounds may be primarily de-pendent on genetic technology, given thecosts and availability of raw materials?
compounds are produced by both methods.However, in most beverage distilling operations,pollution has been reduced to almost zero withthe complete recovery of still slops as animalfeeds of high nutritional value. Such controlprocedures are generally applicable to mostfermentation processes. (App. I-C describes thepollutants that may be produced by currentchemical processes and those expected frombiologically based processes.)
The Environmental Protection Agency hasestimated that the U.S. Government and indus-try combined will spend over $360 billion tocontrol air and water pollution in the decadefrom 1977 through 1986. The share of thechemical and allied industries is about $26 bil-lion. Genetic engineering technology may helpalleviate this burden by offering cleaner proc-esses of synthesis and better biological wastetreatment systems. The monetary savings couldbe tremendous. As pure speculation, if just 5percent of the current chemical industry wereaffected, spending on pollution could be re-duced by about $100 million per year.
may be produced
In principle, virtually all organic compoundscan be produced by biological systems. If thenecessary enzyme or enzymes are not known toexist, a search of the biological world will prob-ably uncover the appropriate ones. Alterna-tively, at least in theory, an enzyme can beengineered to carry out the required reaction.Within this framework, the potential appears tobe limited only by the imagination of the bio-technologist—even though certain chemicalsthat are highly toxic to biological systems areprobably not amenable to production.
Three variables in particular affect theanswer to the second question: the availabilityof an organism or enzymes for the desiredtransformation; the cost of the raw material;and the cost of the production process. Whenspecific organisms and production technologies
Ch. 5—The Chemical Industry ● 93
Table 1 1.—Some Commercial Enzymes and Their Uses
Enzyme Source Industry and application
Amylase . . . . . . . . . . . . . . . . . . .
Bromelin. . . . . . . . . . . . . . . . . . .
Cellulase and hemicellulase . .Dextransucrase. . . . . . . . . . . . .
Ficin . . . . . . . . . . . . . . . . . . . . . .Glucose oxidase (plus catalase
or peroxidase) . . . . . . . . . . . .
Invertase. . . . . . . . . . . . . . . . . . .
Lactase. . . . . . . . . . . . . . . . . . . .
Lipase. . . . . . . . . . . . . . . . . . . . .Papain . . . . . . . . . . . . . . . . . . . . .
Pectinase . . . . . . . . . . . . . . . . . .Penicillinase . . . . . . . . . . . . . . .
Pepsin . . . . . . . . . . . . . . . . . . . . .Protease. . . . . . . . . . . . . . . . . . .
Streptodornase . . . . . . . . . . . . .
Animal(pancreas)
Plant(barley malt)
Fungi (Aspergillus niger,A. oryzae)
Bacteria (Bacillus subtilis)
Plant (pineapple)
Fungi (Aspergillus niger)Bacteria(Leuconostoc mesenteroides)
Plant (fig latex)
Fungi (Aspergillus niger)
Yeast (Saccharomyces cerevisiae)
Yeast (Saccharomyces fragilis)
Fungi (Aspergillus niger)Plant(papaya)
Fungi (Aspergillus niger)Bacteria(Bacillus cereus)
Animal (hog stomach)Animal (pancreas)
Animal (pepsin)Animal (rennin, rennet)Animal (trypsin)Fungi (Aspergillus oryzae)
Bacteria (Bacillus subtilis)
Bacteria (Streptococcus pyrogenes)
Pharmaceutical digestive aidsTextile: desizing agentBaking: flour supplementBrewing, distilling, and industrial alcohol mashingFood: precooked baby foodsPharmaceutical digestive aidsTextile: desizing agentBaking: flour supplementBrewing, distilling, and industrial alcohol mashingFood: precooked baby foods, syrup manufacturePharmaceutical digestive aidsPaper starch coatingsStarch: cold-swelling laundry starchFood: meat tenderizerPharmaceutical digestive aidsFood: preparation of liquid coffee concentratesPharmaceutical preparation of blood-plasma
extenders, and dextran for other usesPharmaceutical: debriding agent
Pharmaceutical test paper for diabetesFood: glucose removal from egg solidsCandy: prevents granulation of sugars in soft-center
candiesFood: artificial honeyDairy: prevents crystallization of lactose in ice cream
and concentrated milkDairy: flavor production in cheeseBrewing: stabilizes chill-proof beerFood: meat tenderizerWine and fruit juice: clarificationMedicine: treatment of allergic reaction to penicillin,
diagnostic agentFood: animal feed supplementDairy: prevents oxidized flavorFood: protein hydrolysatesLeather: batingPharmaceutical: digestive aidsTextile: desizing agentBrewing: beer stabilizerDairy: cheesePharmaceutical: wound debridementBaking: breadFood: meat tenderizerBaking: modification of cracker doughBrewing: clarifierPharmaceutical: wound debridement
SOURCE: David Perlman, “The Fermentation Industries,” American Society for Microbiology News 39:10, 1973, p. 653.
have been developed, the cost of raw materialsbecomes the limiting step in production. If astrain of yeast, for example, produces 5 percentethanol using sugar as a raw material, the proc-ess might become economically competitive ifthe cost of sugar drops or the price of petro-leum rises. Even if prices remain stable, themicro-organisms might be genetically improvedto increase their yield; genetic manipulationmight solve the problem of an inefficient
organism. Finally, the production process itselfis a factor. After fermentation, the desired prod-uct must be separated from the other com-pounds in the reaction mixture. As an aid to re-covery, the production conditions might bealtered and improved to generate more of a de-sired compound.
More than one raw material can be used in afermentation process. If, in the case of ethanol,
94 ● Impacts of Applied Genetics—Micro-Organisms, Plants, and Animals
the price of sucrose (from sugarcane or sugarbeets) is not expected to change, the productiontechnology is being run at optimum efficiency,and the micro-organism is producing as muchethanol as it can, the hurdle to economic com-petitiveness might be overcome if a less expen-sive raw material—cellulose, perhaps—wereused. But cellulose cannot be used in its naturalstate: physical, chemical, or biological methodsmust be devised to break it down to its glucose(also a sugar) components.
The constraints vary from compound to com-pound. But even though the role of geneticsmust be examined on a product-by-product ba-sis, certain generalizations can be made. Over-all, genetic engineering will probably have animpact on three processes:
●
●
●
Aerobic fermentation, which produces en-zymes, vitamins, pesticides, growth regula-tors, amino acids, nucleic acids, and otherspeciality chemicals, is already well-estab-lished. Its use should continue to grow. Al-ready, complex biochemical like antibiot-ics, growth factors, and enzymes are madeby fermentation. Amino acids and nucleo-tides—somewhat less complicated mole-cules—are sometimes produced by fer-mentation. Their production is expected toincrease.Anaerobic fermentation, which producesorganic acids, methane, and solvents, is theindustry’s area of greatest current growth.Already, 40 percent of the ethanol man-ufactured in the United States is producedin this way. The main constraint on theproduction of other organic acids and sol-vents is the need for cheaper methods forconverting cellulose to fermentable sugars.Chemical modification of the fermentationproducts of both aerobic and anaerobicfermentation, which to date has rarelybeen used on a commercial scale, is ofgreat interest. (See table 12.) Chemical pro-duction technologies that employ high tem-peratures and pressures might be replacedby biological technologies operating at at-mospheric pressure and ambient tempera-ture. A patent application has already beenfiled for the biological production of one of
Table 12.—Expansion of Fermentation Intothe Chemical Industry
Examples
Aerobic fermentationEnzymes . . . . . . . . . . . . . . . . Amylases, proteasesVitamins . . . . . . . . . . . . . . . . Riboflavin B,zPesticides. . . . . . . . . . . . . . . Bacillus thuringiensisGrowth regulators . . . . . . . . GibberellinAmino acids . . . . . . . . . . . . . Glutamic, IysineNucleic acidsAcids. . . . . . . . . . . . . . . . . . . Malic acid, citric acid
Anaerobic fermentationSolvents . . . . . . . . . . . . . . . . Ethanol, acetone, n-butanolAcids. . . . . . . . . . . . . . . . . . . Acetic, propionic, acrylic
SOURCE: Office of Technology Assessment.
these products, ethylene glycol, by theCetus Corp. in Berkeley, Calif. The processis claimed to be more energy efficient andless polluting. If it proves successful whenrun at an industrial scale, the technologycould become significant to a [J. S. markettotaling $21/2 billion per year.
The chemical industry produces a variety oflikely targets for biotechnology. Tables I-B-27through 1-B-32 in appendix I-B present projec-tions of the potential economic impacts of ap-plied genetics on selected compounds thatrepresent large markets, and the time framesfor potential implementation. Table I-B-7 listsone large group of organic chemicals that wereidentified by the Genex Corp. and Massachu-setts Institute of Technology (MIT) as amenableto biotechnological production methods. Theyare in agreement on about 20 percent of theproducts cited, which underscores the uncer-tain nature of attempting to predict so far intothe future.
Fertilizers, polymers, and pesticides
Gaseous ammonia is used to produce nitrogenfertilizers. About 15 billion tonnes of ammoniawere produced chemically for this purpose, in1978; the process requires large amounts ofnatural gas. Nitrogen can also be converted, or“fixed,” to ammonia by enzymes in micro-orga-nisms; about 175 billion tonnes are fixed peryear. For example, one square yard of landplanted with certain legumes (such as soybeans)can fix up to 2 ounces of nitrogen, using bac-
Ch. 5—The Chemical Industry ● 95
teria associated with their roots. Currently, mi-crobial production of ammonia from nitrogen isnot economically competitive. Aside from thedifficulties associated with the enzyme’s sen-sitivity to oxygen and the near total lack ofunderstanding of its mechanism, it takes theequivalent of the energy in 4 kilograms (kg) ofsugar to make 1 kg of ammonia. Since ammoniacosts $0. 13/kg and sugar costs $0.22/kg, it is un-likely that the chemical process will be replacedin the near future. On the other hand, the genesfor nitrogen fixation have now been transferredinto yeast, opening up the possibility that agri-culturally useful nitrogen can be made by fer-mentation.
A large segment of the chemical industry en-gaged in the manufacture of polymers is shownin table 13. A total of 4.3 million tonnes offibers, 12 million tonnes of plastics, and I. I mil-lion tonnes of synthetic rubber were producedin the United States in 1978. All were derivedfrom petroleum, with the exception of the lessthan 1 percent derived from cellulose fibers.The most likely ones are polyamides (chemicallyrelated to proteins), acrylics, isoprene-type rub-ber, and polystyrene, Because most monomers,the building blocks of polymers, are chemicallysimple and are presently available in high yieldfrom petroleum, their microbial production inthe next decade is unlikely.
While biotechnoloqy is not ready to replacethe present technology, its eventual impact onpolymer production will probably be large.Biopolymers represent a new way of thinking.Most of the important constituents of cells arepolymers: proteins (polypeptides from aminoacid monomers), polysaccharides (from sugarmonomers), and polynucleotides (from nucleo-tide monomers). Since cells normally assemblepolymers with extreme specificity, the ideal in-dustrial process would imitate the biologicalproduction of polymers in all possible respects—using a single biological machine to convert araw material, e.g., a sugar, into the monomer topolymerize it, then to form the final product. Amore likely application is the development ofnew monomers for specialized applications.Polymer chemistry has largely consisted of thestudy of how their properties can be modified.
Table 13.—The Potential of Some Major PolymericMaterials for Production Using Biotechnology
Domestic production 1978Product (thousand tonnes)PlasticsThermosetting resins
Epoxy. . . . . . . . . . . . . . . . . . . . . . . . .Polyester. . . . . . . . . . . . . . . . . . . . . .Urea. . . . . . . . . . . . . . . . . . . . . . . . . .Melamine . . . . . . . . . . . . . . . . . . . . .Phenolic . . . . . . . . . . . . . . . . . . . . . .
Thermoplastic resinsPolyethylene
Low density . . . . . . . . . . . . . . . . .High density. . . . . . . . . . . . . . . . .
Polypropylene . . . . . . . . . . . . . . . . .Polystyrene. . . . . . . . . . . . . . . . . . . .Polyamide, nylon type. . . . . . . . . . .Polyvinyl alcohol . . . . . . . . . . . . . . .Polyvinyl chloride. . . . . . . . . . . . . . .Other vinyl resins. . . . . . . . . . . . . . .
FibersCellulosic fibers
Acetate . . . . . . . . . . . . . . . . . . . . . . .Rayon . . . . . . . . . . . . . . . . . . . . . . . .
Noncellulosic fibersAcrylic. . . . . . . . . . . . . . . . . . . . . . . .Nylon. . . . . . . . . . . . . . . . . . . . . . . . .Olefins. . . . . . . . . . . . . . . . . . . . . . . .Polyester. . . . . . . . . . . . . . . . . . . . . .Textile glass . . . . . . . . . . . . . . . . . . .Other . . . . . . . . . . . . . . . . . . . . . . . . .
RubbersStyrene-butadiene. . . . . . . . . . . . . . . .Polybutadiene . . . . . . . . . . . . . . . . . . .Butyl . . . . . . . . . . . . . . . . . . . . . . . . . . .Nitrile. . . . . . . . . . . . . . . . . . . . . . . . . . .Polychlorophene . . . . . . . . . . . . . . . . .Ethylene-propylene . . . . . . . . . . . . . . .Polyisoprene. . . . . . . . . . . . . . . . . . . . .
135544504
90727
3,2001,8901,3802,680
12457
2,57588
139269
3271,148
3111,710
4187
6281706933727862
SOURCE: Office of Technology Assessment.
Conceivably, biotechnology could enable themodification of their function and form.
Pesticides include fungicides, herbicides, in-secticides, rodenticides, and related productssuch as plant growth regulators, seed disinfec-tants, soil conditioners, and soil fumigants. Thelargest market (roughly $500 million annually)involves the chemical and microbial control ofinsects. Although microbial insecticides havebeen around for years, they comprise only 5percent of the market. However, recent suc-cesses in developing viruses and bacteria thatproduce diseases in insects, and the negativepublicity given to chemical insecticides, haveencouraged the use of microbial insecticides.
96 . Impacts of Applied Genetics—Micro-Organisms, Plants, and Animals
The other two species can be produced by con-Ventional fermentation techniques. They havebeen useful because they form spores that canbe mass-produced easily and are stable enoughto be handled commercially. The actual sub-stances that cause toxicity to the insect are tox-ins synthesized by the microbes.
Genetic engineering should make it possibleto construct more potent bacterial insecticidesby increasing the dosage of the genes that codefor the synthesis of the toxins involved. Mix-tures of genes capable of directing the synthesisof various toxins might also be produced.
Constraints on biological production techniques ____The chief impediments to using biological
production technology are associated with theneed for biomass. 2 They include:
●
●
●
●
●
●
●
competition with food needs for starch andsugar;cyclic availability;biodegradability and associated storageproblems;high moisture content for cellulosics, andhigh collection and storage costs;mechanical processing for cellulosics;the heterogeneous nature of cellulosics (mix-tures of cellulose, hemicellulose, and lig-nin); andThe need for disposal of the nonferment-able port ions of the biomass.
For food-related biomass sources, such as su-gar, corn, and sorghum, few technological bar-riers exist for conversion to fermentable sugars;but subsidies are needed to make the fermenta-tion of sugars as profitable as their use as food.For cellulosic biomass sources such as agricul-tural wastes, municipal wastes, and wood, tech-nological barriers exist in collection, storage,pretreatment, fermentation, and waste disposal.In addition, biomass must always be trans-formed into sugars by either chemical or en-zymatic processes before fermentation canbegin.
‘ljnf~r,qv F’r(ml ~io/(J,gif’if/ PrOct’s.st*,s, 01). (’it.
A second major impediment is associatedwith the purification stage of production. Mostchemical products of fermentation are presentin extremely dilute solutions, and concentratingthese solutions to recover the desired product ishighly energy-intensive. Problems of technologyand cost will continue to make this stage an im-portant one to improve.
The developments in genetics show greatpromise for creating more versatile micro-orga-nisms, but they do not by themselves produce acheaper fuel or plastic. Associated technologiesstill require more efficient fermentation facil-ities and product separation processes; mi-crobes may produce molecules, but they willnot isolate, purify, concentrate, mix, or packagethem for human use.
The interaction between genetic engineeringand other technologies is illustrated by theproblems of producing ethanol by fermenta-tion. The case study presented in appendix I-Didentifies those steps in the biomass-to-ethanolscheme that need technological improvementsbefore the process can become economical.
Genetic engineering is expected to reducecosts in many production steps. For certainones—such as the pretreatment of the biomassto make it fermentable—genetics will probablynot play a role: physical and chemical technol-ogies will be responsible for the greatest ad-vances. For others, such as distillation, genetic
Ch. 5—The Chemical Industry . 97
technologies should make it possible to engineerorganisms that can ferment at high tempera-tures (82° to 85° C) so that the fermentation andat least part of the distillation can both takeplace in the same reactor. Various technol-
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ill IIW g(~tlus [,’l(jslri(fiunl [i. (’., (;. fhf’rr?~()(:f;ll[~n~). Ill i![ldil ion, gciwl i-(’ill 11’ wlgilwf’1’(~d ol’~illlisllls, (Ies(’ril)e(i ii!+ il (’1’OSS 1)(’ltt’tWll V(!ilSIS
;111( i I I)ol’lllol)ll” i] it’ I)il(’1 f>l’lil, (’iIll I’pl’lllf)tll il I 700 (:.
An overview of impactsThe cost of raw materials may become cheap-
er than the petroleum now used—especially ifcellulose conversion technologies can be devel-oped. The source of raw materials would alsobe broader since several kinds of biomass couldbe interchanged, if necessary. For small quan-tities of chemicals, the raw material supplywould be more dependable, particularly be-cause of the domestic supply of available bio-mass. For substances produced in large quanti-ties, such as ethanol, the supply of biomasscould limit the usefulness of biotechnology.
Raw materials, such as organic wastes, couldbe processed both to produce products andreduce pollution. Nevertheless, the impact ontotal imported petroleum will be low. Estimatesof the current consumption of petroleum as araw material for industrial chemicals is approx-imately 5 to 8 percent of the total imported.
Impacts on the process include relativelycheaper production costs for selected com-pounds. For these, lower temperatures andpressures can be used, suggesting that the proc-esses might be safer. Chemical pollution frombiotechnology may be lower, although methodsof disposal or new uses must be found for themicro-organisms used in fermentation. Finally,the biological processes will demand the devel-opment of new technologies for the separationand purification of the products.
impacts on the products include both cheaperexisting chemicals as well as entirely new prod-ucts. Since biotechnology is the method ofchoice for producing enzymes, new uses for en-
ogies, such as the immobilization of whole cellsin reactor columns, could be developed in paral-lel with genetic technologies to increase the sta-bility of cells in fermenters.
‘l”lIt? ild\’illltit#?S Ot” SllCh Ilwrnmphilic I“t’l’lll(’lllilt iollS ill’t’ signif’i-
(’illll: I’t?l’lllt%ltiitioll I inw is CollSi&Will)l}” l’t’(111(’tXl; IIIP risk ot (’oll-
Iillllillill ion i s llt?ill’1.V f?litllitlille(l: illl(l cooling” t.t’(lltil.(’lllt’tlls ill’(’
I[)w’t?t’ (111(+ 10 llle lli@el. lt?lll~t?l’iitll l’(’ ot” III(’ t’msnlt’nt in~ 1)1’0111.
zymes may expand and drive this sector of theindustry.
Impacts on other industries
Although genetic engineering will developnew techniques for synthesizing many sub-stances, the direct displacement of any presentindustry appears to be doubtful: Genetic engi-neering should be considered simply another in-dustrial tool. As such, any industry’s responseshould be to use this technique to maintain itspositions in its respective markets. The point isillustrated by the variety of companies in thepharmaceutical, chemical, and energy indus-tries that have invested in or contracted withgenetic engineering firms. Some large com-panies are already developing inhouse geneticengineering research capabilities.
The frequent, popular reference to the small,innovative “genetic engineering companies” as amajor new industry is somewhat misleading.The companies (see table 14) arose primarily toconvert micro-organisms with little commercialuse into micro-organisms with commercial po-tential. A company such as the Cetus Corp. ini-tially used mutation and selection to improvestrains, whereas other pioneers such as Genen-tech, Inc., Biogen, S. A., and Genex Corp. werefounded to exploit recombinant DNA (rDNA)technology. Part of their marketing strategy in-cludes the sale or licensing of genetically engi-neered organisms to large established commer-cial producers in the chemical, pharmaceutical,food, energy, and mining industries. Each engi-
98 . Impacts of Applied Genetics—Micro-Organisms, Plants, and Animals
Table 14.—Some Private Companies With Biotechnology Programs
Approximate Research capacityCompany Founded employees 1979 Ph. D.s 1979 Recombinant DNA HybridomasAtlantic Antibodies. . . . . . . . . . . . . . . . . . 1973 50 2 xBethesda Research Laboratories . . . . . . 1976 130 x xBiogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978 30 (50b) (18b) (3)(5)
x xBens Bio Logicals . . . . . . . . . . . . . . . . . . . 1979 15 10 x xCentocor. . . . . . . . . . . . . . . . . . . . . . . . . . . 1979 20(1)-10(4) xCetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1972 250 50 x xClonal Research . . . . . . . . . . . . . . . . . . . . 1979 6 1 xCollaborative ResearchC. . . . . . . . . . . . . . 1961 85 15 x x
(Collaborative Genetics) . . . . . . . . . . . . (1979) (4) (3) xGenentech . . . . . . . . . . . . . . . . . . . . . . . . . 1976 90 30 xGenex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977 30 12 xHybritech . . . . . . . . . . . . . . . . . . . . . . . . . . 1978 3 3(1)
6 xMolecular Genetics. . . . . . . . . . . . . . . . . . 1979 6(4) x xMonoclinal Antibodies. . . . . . . . . . . . . . . 1979 6 xNewEngland Biolabs . . . . . . . . . . . . . . . . 1974 22(22)-5 (4) x
q=.E~r9t~t~co. estimates.bEXwtedby~cem~rl~.ccollaboratlve Research isamajorowner of Collaborative Genetics. Thedivision batweenthem isnotyetdistinct.SOURCES: (l)Sc/ence206, p.692.693, 1960(52 peopletoexpandto100 by1961).
(2) Science 206, p. 692-693, 19S0 (20 senior peraona).(3) Science 206, p. 692-693, 1960(16 scientists, 30 employees).(4) Dun & Bradstreet, Inc.(5) Chemlcalarrd Engineering News, Mar. 19,1960.Office of Technology Assessment.
neering firm also intends to manufacture someproducts itself. It is likely that the products re-served for inhouse manufacture will be low-volume, high-priced compounds like interferon.
Genetic engineering by itself is a relativelysmall-scale laboratory operation. Consequently,genetic engineering firms will continue to offerservices to companies that do not intend todevelop this capacity in their own inhouse lab-oratories. Specifically, a genetic engineeringcompany may contract with a firm to develop abiological production method for its products.At the same time, larger companies might estab-lish inhouse staffs to develop biological methodsfor both old and new products. (Several largercompanies already have more inhouse geneticengineering personnel than some of the inde-pendent genetic engineering companies.)
In addition, suppliers of genetic raw materialsmay decide to expand into the production ofgenetically engineered organisms. Suppliers ofrestriction endonuclease enzymes for example,which are used in constructing rDNA, havealready entered the field. Diagnostic firms coulddevelop new bioassays for which they them-selves would guarantee a market. Finally, com-panies with byproducts or waste products are
beginning to examine the possibility of convert-ing them into useful products. This approach(which is somewhat more developed in Europe)assumes that with the proper technology thewaste materials can become a resource.
Some industries, including manufacturers ofagitators (drives), centrifuges, evaporators, fer-menters, dryers, storage tanks and processvessels, and control and instrumentation sys-tems, might profit by producing equipmentassociated with fermentation.
Impacts on university research
From the beginning, genetic engineeringfirms established strong ties with universities.These were responsible for providing most ofthe scientific knowledge that formed the basisfor applied genetics as well as the initial scien-tific workforce:
Cetus Corp. established a pattern by re-cruiting a prestigious Board of ScientificAdvisors who remain in academic posi-tions.Genentech, Inc., cofounded by a professorat the University of California at San Fran-
Ch. 5—The Chemical Industry . 99
●
●
●
cisco, initially depended largely on outsidescientists.Biogen, S. A., was organized by professorsat Harvard and MIT plus six European sci-entists, and placed R&D contracts with aca-demic researchers.Collaborative Genetics has a Nobel prizewinner from MIT as the chairman of its sci-entific advisory board.Hybritech, Inc., has as its scientific nucleusa University of California, San Diego, pro-fessor complemented by scientists at theSalk Institute.
In addition to these companies, others have alsobeen establishing closer ties with the academiccommunity.
Much of the research that will be useful to in-dustry will continue to be carried out in univer-sity laboratories. At present, it is often difficultto decide whether a research project should beclassified as “basic” (generally more interestingto an academic researcher) or “applied” (gener-ally more interesting to industry). E.g., a changein the genetic code, which increases gene activi-ty, would be just as exciting to a basic scientistas to an industrial one.
This dialog between the universities and in-dustry—both through formal and informal ar-rangements –has fostered innovation. Althoughthe number of patents applied for is not a directreflection of the level of innovation, it is still oneindication. By the end of 1980, several hundredpatent applications were filed for geneticallyengineered micro-organisms, their products,and their processes.
University research has clearly affected in-dustrial development, and has in turn been af-fected by industry. Although the benefits areeasily recognized, some drawbacks have beensuggested. The most serious is the concern thatuniversity scientists will be restrained in theiracademic pursuits and in their exchange of in-formation and research material. To date, anec-dotal information suggests that some scientistsare being more circumspect about sharing in-formation. Still, secrecy is not new to highlycompetitive areas of biomedical research. In ad-dition, scientists in other academic disciplines
useful to industry-such as chemistry and phys-ics—have managed to achieve a balance be-tween secrecy and openness.
The social impacts of localindustrial activity
Despite the extensive media coverage ofrDNA and other forms of genetic engineering,there is little evidence that people who live nearcompanies using such techniques are still great-ly concerned about possible hazards. This maybe partly owing to a lack of awareness that aparticular company is doing genetic researchand partly because companies thus far haveadhered to the National institutes of Health(NIH) Guidelines. Some companies have placedindividuals on their institutional biosafety com-mittees who are respected and trusted mem-bers of the local community. By involving thelocal citizens with no vested corporate interest,a mechanism for oversight has been provided.(For a more detailed discussion, see ch. 11.)
Impacts on manpower
Two types of impacts on workers can be ex-pected:
● The creation of jobs that replace those heldby others. E.g., a worker involved inchemical production might be replaced byone producing the same product biologi-cally.
● The creation of new jobs.
Workers in three categories would be af-fected:
● those actually involved in the fermentation-production phase of the industry;
● those involved in the R&D phase of the in-dustry, particularly professionals; and
. those in support industries.
Projections of manpower requirements areonly as accurate as the projections of the level ofindustrial activity. In the past 5 years, about 750new jobs have been created within the small ge-netic engineering firms (including monoclinalantibody producers). Of these, approximatelyone-third hold Ph. D. degrees.
100 . Impacts of Applied Genetics—Micro-0rganisms, Plants, and Animals
Data obtained through an (OTA survey of 284firms indicate that the pharmaceutical industryemploys the major share of personnel workingin applied genetics programs. (See table 15. ) Theaverage number of Ph. D.s in each industry isgiven in table 16. A rough estimate of profes-sional scientific manpower at this level includes:6 in food, 45 in chemical, 120 in pharmaceutical,and 18 in specialty chemicals-a total of 189. Ifthe number of research support personnel isapproximately twice the number of Ph. D.s, thetotal rises to about 570. If $165,000 per year isrequired to support one Ph. D. in industry, thetotal value of such manpower is approximately$31 million.
Estimates of the number of companies en-gaged in applied genetics work in 1980 can becompared with the total number of firms withfermentation activities. A tabulation of firms ona worldwide basis in 1977 revealed 145 com-panies, of which 27 were American. (See table17. ) These companies produced antibiotics, en-zymes, solvents, vitamins and growth factors,
Table 15.—Distribution of Applied GeneticsActivity in Industry
Distribution of appliedgenetics activity by Percent
Classification company classa of totalFood . . . . . . . . . . . . . . (6146) 13Chemical . . . . . . . . . . (9/52) 17Pharmaceutical . . . . . (12/25) 48Specialty chemicalb . (6/68) 9
algnoreg small firing specializing in genetic research.bFood ingredients, reagents, enzymes.SOURCE: Office of Technology Assessment.
Table 16.—Manpower (Iow.(average)-high) Distributionof a Firm With Applied Genetics Activity
Ph. D. M.S. BachelorsFood. . . . . . . . . . . . . . . . . ql)-2Chemical . . . . . . . . . . . . . 3-(5)-7Pharmaceutical. . . . . . . 2-(10)-24Specialty. . . . . . . . . . . . . l-(3)-8Biotechnology
Genetic engineering. 3-(15)-32Hybridoma. . . . . . . . . . l-(3)-6Other . . . . . . . . . . . . . . O-(2)-4
Average . . . . . . . . . .1-(6)-12
0-(1 )-20-(1 )-2l-(4)-9l-(3)-4
2-(1 1)-200-(2)-02-(4)-6l-(4)-6
O-(2)-82-(5)-71-(8)-202-(2)-4
5-(15)-250-(20)-0
8-(10)-133-(8)-12
SOURCE: Office of Technology Assessment.
Table 17.—lndex to Fermentation Companies
1. Abbott Laboratories, North Chicago, 111.2. American Cyanamid, Wayne, N.J.3. Anheuser-Busch, Inc., St. Louis, Mo.4. Bristol-Myers Co., Syracuse, N.Y.5. Clinton Corn Processing Co., Clinton, Iowa6. CPC International, Inc., Argo, Ill.7. Dairyland Laboratories, Inc., Waukesha, Wis.8. Dawe’s Laboratories, Inc., Chicago Heights, Ill.9. Grain Processing Corp., Muscatine, Iowa
10. Hoffman-LaRoche, Inc., Nutley, N.J.11. IMC Chemical Group, Inc., Terre Haute, Ind.12. Eli Lilly & Co., Indianapolis, Ind.13. Merck & Co., Inc., Rahway, N.J.14. Miles Laboratories, Inc., Elkhart, Ind.15. Parke, Davis & Co., Detroit, Mich.16. S. B. Penick & Co., Lyndhurst, N.J.17. Pfizer, Inc., New York, N.Y.18. Premier Malt Products, Inc., Milwaukee, Wis.19. Rachelle Laboratories, Inc., Long Beach, Cal if.20. Rohm & Haas, Philadelphia, Pa.21. Schering Corp., Bloomfield, N.J.22. G. D. Searle & Co., Skokie, Ill.23. E. R. Squibb& Sons, Inc., Princeton, N.J.24. Standard Brands, Inc., New York, N.Y.25. Stauffer Chemical Co., Westport, Corm.26. Universal Foods Corp., Milwaukee, Wis.27. The Upjohn Co., Kalamazoo, Mich.28. Wallerstein Laboratories, Inc., Morton Grove, Ill.29. Wyeth Laboratories, Philadelphia, Pa.
SOURCE: Office of Technology Assessment.
nucleosides, amino acids, and miscellaneousproducts. (See table 18.) The only chemical firmlisted was the Stauffer Chemical Co. Ten firmsare listed as having the ability to produce foodand feed yeast. (See table 19. ) Correcting forfirms listed twice, at least 38 U.S. firms wereengaged in significant fermentation activity forcommercial products, excluding alcoholic bev-erages, in 1977. Not all have research expertisein fermentation or biotechnology, much less aregular genetics program: 10 to 20 were in thechemical industry; 25 to 40 in fermentation (en-zyme, pharmaceutical, food, and specializedchemicals); and 10 to 15 in biotechnology (genet-ic engineering)—or about 45 to 75 firms in all.
If average manpower numbers are used, thetotal number of professionals involved in com-mercial applied genetics research is:
Ph. D.s: 300-450Others: 600-900
900-1,350
The number of workers that will be involvedin the production phase of biotechnology repre-
Ch.5—The Chemical Industry ● 101
Table 18.-Fermentation Products and Producers
Product Some producers Product Some producers
Amino acidsL-alanine. . . . . . . . . . . . . . . . . . . . . . . . . . .L-arginine. . . . . . . . . . . . . . . . . . . . . . . . . .L-aspartic acid. . . . . . . . . . . . . . . . . . . . . .L-citrulline . . . . . . . . . . . . . . . . . . . . . . . . .L-glutarnic acid . . . . . . . . . . . . . . . . . . . . .L-glutamine . . . . . . . . . . . . . . . . . . . . . . . .L-glutathione . . . . . . . . . . . . . . . . . . . . . . .L-histidine . . . . . . . . . . . . . . . . . . . . . . . . .L-homoserine. . . . . . . . . . . . . . . . . . . . . . .L-isoleucine . . . . . . . . . . . . . . . . . . . . . . . .L-leucine. . . . . . . . . . . . . . . . . . . . . . . . . . .L-lysine . . . . . . . . . . . . . . . . . . . . . . . . . . . .L-methionine . . . . . . . . . . . . . . . . . . . . . . .L-ornithine . . . . . . . . . . . . . . . . . . . . . . . . .L-phenylalanine. . . . . . . . . . . . . . . . . . . . .L-proline. .... . . . . . . . . . . . . . . . . . . . . .L-serine. . . . . . . . . . . . . . . . . . . . . . . . . . . .L-threonine. .. . . . . . . . . . . . . . . . . . . . . .L-tryptophan. . . . . . . . . . . . . . . . . . . . . . .L-tyrosine . . . . . . . . . . . . . . . . . . . . . . . . . .L-valine. ..... . . . . . . . . . . . . . . . . . . . . .
Miscellaneous products and processesAcetoin . . . . . . . . . . . . . . . . . . . . . . . . . . . .Acyloin . . . . . . . . . . . . . . . . . . . . . . . . . . . .Anka-pigment(red) . . . . . . . . . . . . . . . . . .Blue cheese flavor. . . . . . . . . . . . . . . . . . .Desferrioxamine . . . . . . . . . . . . . . . . . . . .Dihydroxyacetone . . . . . . . . . . . . . . . . . . .Dextran . . . . . . . . . . . . . . . . . . . . . . . . . . . .Diacetyl (from acetoin) . . . . . . . . . . . . . . .Ergocornine . . . . . . . . . . . . . . . . . . . . . . . .Ergocristine . . . . . . . . . . . . . . . . . . . . . . . .Ergocryptine . . . . . . . . . . . . . . . . . . . . . . .Ergometrine . . . . . . . . . . . . . . . . . . . . . . . .Ergotamine. . . . . . . . . . . . . . . . . . . . . . . . .Bacillus thuringiensis insecticide. . . . . .Lysergic acid . . . . . . . . . . . . . . . . . . . . . . .Paspalic acid . . . . . . . . . . . . . . . . . . . . . . .Picibanil . . . . . . . . . . . . . . . . . . . . . . . . . . .Ribose. . . . . . . . . . . . . . . . . . . . . . . . . . . . .Scteroglucan . . . . . . . . . . . . . . . . . . . . . . .Sorbose(from sorbitol). . . . . . . . . . . . . . .Starter cultures . . . . . . . . . . . . . . . . . . . . .Sterol oxidations.. . . . . . . . . . . . . . . . . . .Steroid oxidations. . . . . . . . . . . . . . . . . . .Xanthan . . . . . . . . . . . . . . . . . . . . . . . . . . .
AntibioticsAdriamycin. . . . . . . . . . . . . . . . . . . . . . . . .Amphomycin . . . . . . . . . . . . . . . . . . . . . . .Amphotericin B.. . . . . . . . . . . . . . . . . . . .Avoparcin . . . . . . . . . . . . . . . . . . . . . . . . . .Azalomycin F . . . . . . . . . . . . . . . . . . . . . . .Bacitracin. . . . . . . . . . . . . . . . . . . . . . . . . .Bambermycins. . . . . . . . . . . . . . . . . . . . . .Bicyclomycin. . . . . . . . . . . . . . . . . . . . . . .Blasticidin S. . . . . . . . . . . . . . . . . . . . . . . .Bleomycin . . . . . . . . . . . . . . . . . . . . . . . . .CactinomycinCandicidin B. . . . . . . . . . . . . . . . . . . . . . . .Candidin . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
13
7
17,21,28
1
10,177,13,1422,2721,23,27,2913,17
232
11,16,17
16
Capreomycin . . . . . . . . . . . . . . . . . . . . . . .Cephalosporins. . . . . . . . . . . . . . . . . . . . .Chromomycin A3 . . . . . . . . . . . . . . . . . . . .Colistin . . . . . . . . . . . . . . . . . . . . . . . . . . . .Cycloheximide. . . . . . . . . . . . . . . . . . . . . .Cycloserine . . . . . . . . . . . . . . . . . . . . . . . .Dactinomycin. . . . . . . . . . . . . . . . . . . . . . .Daunorubicin. . . . . . . . . . . . . . . . . . . . . . .Destomycin . . . . . . . . . . . . . . . . . . . . . . . .Enduracidin . . . . . . . . . . . . . . . . . . . . . . . .Erythromycin . . . . . . . . . . . . . . . . . . . . . . .Fortimicins. . . . . . . . . . . . . . . . . . . . . . . . .Fumagiliin . . . . . . . . . . . . . . . . . . . . . . . . .Fungimycin . . . . . . . . . . . . . . . . . . . . . . . .Fusidic acid . . . . . . . . . . . . . . . . . . . . . . . .Gentamicins. . . . . . . . . . . . . . . . . . . . . . . .Gramicidin A . . . . . . . . . . . . . . . . . . . . . . .Gramicidin J(S) . . . . . . . . . . . . . . . . . . . . .Griseofulvin . . . . . . . . . . . . . . . . . . . . . . . .Hygromycin B . . . . . . . . . . . . . . . . . . . . . .Josamycin . . . . . . . . . . . . . . . . . . . . . . . . .Kanamycins. . . . . . . . . . . . . . . . . . . . . . . .Kasugamycin. . . . . . . . . . . . . . . . . . . . . . .Kitasatamycin. . . . . . . . . . . . . . . . . . . . . .Lasalocid . . . . . . . . . . . . . . . . . . . . . . . . . .Lincomycin. . . . . . . . . . . . . . . . . . . . . . . . .Lividomycin . . . . . . . . . . . . . . . . . . . . . . . .Macarbomycin. . . . . . . . . . . . . . . . . . . . . .Mepartricin. . . . . . . . . . . . . . . . . . . . . . . . .Midecamycin. . . . . . . . . . . . . . . . . . . . . . .Mikamycins . . . . . . . . . . . . . . . . . . . . . . . .Mithramycin. . . . . . . . . . . . . . . . . . . . . . . .Mitomycin C. . . . . . . . . . . . . . . . . . . . . . . .Mocimycin . . . . . . . . . . . . . . . . . . . . . . . . .Monensin . . . . . . . . . . . . . . . . . . . . . . . . . .Myxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Neornycins. ... . . . . . . . . . . . . . . . . . . . .Novobiocin. . . . . . . . . . . . . . . . . . . . . . . . .Nystatin . . . . . . . . . . . . . . . . . . . . . . . . . . .Oleandomycin. . . . . . . . . . . . . . . . . . . . . .Oligomycin. . . . . . . . . . . . . . . . . . . . . . . . .Paromomycins. . . . . . . . . . . . . . . . . . . . . .Penicillin G. . . . . . . . . . . . . . . . . . . . . . . . .Penicillin V . . . . . . . . . . . . . . . . . . . . . . . . .Penicillins(semisynthetic). . . . . . . . . . . .Pentamycin . . . . . . . . . . . . . . . . . . . . . . . .Pimaricin . . . . . . . . . . . . . . . . . . . . . . . . . .Polymyxins. . . . . . . . . . . . . . . . . . . . . . . . .Polyoxins . . . . . . . . . . . . . . . . . . . . . . . . . .Pristinamycins. . . . . . . . . . . . . . . . . . . . . .Quebemycin. . . . . . . . . . . . . . . . . . . . . . . .Ribostamycin. . . . . . . . . . . . . . . . . . . . . . .Rifamycins. . . . . . . . . . . . . . . . . . . . . . . . .Sagamicin. . . . . . . . . . . . . . . . . . . . . . . . . .Salinomycin, . . . . . . . . . . . . . . . . . . . . . . .Siccanin . . . . . . . . . . . . . . . . . . . . . . . . . . .Siomycin. . . . . . . . . . . . . . . . . . . . . . . . . . .Sisomicin ... . . . . . . . . . . . . . . . . . . . .Spectinomycin. . . . . . . . . . . . . . . . . . . . . .Streptomycin. . . . . . . . . . . . . . . . . . . . . .TetracyclinesClortetracycline. . . . . . . . . . . . . . . . . . . . .
4,12
271113
17,27
2128
12
4
1027
174
1016,17,23,27272317
154,12,13,17,23,291,4,12,17,23,294,13,17,23,29
17
212713,17,29
19
76-565 0 - 81 - 8
102 . Impacts of Applied Genetics—Micro-Organkms, Plants, and Animals
Table 18.-Fermentation Products and Producers
Product Some producers Product Some producers
Demeclocycline. . . . . . . . . . . . . . . . . . . . .Oxytetracycline. . . . . . . . . . . . . . . . . . . . .Tetracycline. . . . . . . . . . . . . . . . . . . . . . . .Tetranactin. . . . . . . . . . . . . . . . . . . . . . . . .Thiopeptin . . . . . . . . . . . . . . . . . . . . . . . . .Thiostrepton . . . . . . . . . . . . . . . . . . . . . . .Tobramycin . . . . . . . . . . . . . . . . . . . . . . . .Trichomycin. . . . . . . . . . . . . . . . . . . . . . . .Tylosin . . . . . . . . . . . . . . . . . . . . . . . . . . . .Tyrothricin ..... . . . . . . . . . . . . . . . . . . .Tyrocidine . . . . . . . . . . . . . . . . . . . . . . . . .Uromycin . . . . . . . . . . . . . . . . . . . . . . . . . .Vaildamycin . . . . . . . . . . . . . . . . . . . . . . . .Vancomycin . . . . . . . . . . . . . . . . . . . . . . . .Variotin. . . . . . . . . . . . . . . . . . . . . . . . . . . .Viomycin. .. ..... . . . . . . . . . . . . . . . . .Virginiamycin. . . . . . . . . . . . . . . . . . . . . .EnzymesAmylases . . . . . . . . . . . . . . . . . . . . . . . . . .Amyloglucosidase. . . . . . . . . . . . . . . . . . .Anticyanase. . . . . . . . . . . . . . . . . . . . . . . .L-asparaginase . . . . . . . . . . . . . . . . . . . . .Catalase . . . . . . . . . . . . . . . . . . . . . . . . . . .Cellulase. . . . . . . . . . . . . . . . . . . . . . . . . . .Dextranase. . . . . . . . . . . . . . . . . . . . . . . . .‘Diagnostic enzymes’ . . . . . . . . . . . . . . . .Esterase-lipase . . . . . . . . . . . . . . . . . . . . .Glucanase . . . . . . . . . . . . . . . . . . . . . . . . .Glucose dehydrogenase. . . . . . . . . . . . . .Glucose isomerase . . . . . . . . . . . . . . . . . .Glucose oxidase . . . . . . . . . . . . . . . . . . . .Glutamic decarboxylase. . . . . . . . . . . . . .Hemi-celiulase. . . . . . . . . . . . . . . . . . . . . .Hespiriginase. . . . . . . . . . . . . . . . . . . . . . .lnvertase. . . . . . . . . . . . . . . . . . . . . . . . . . .
217,192,4,17,19,23,27
2312
1216,28
12
5,19,20,24,285,6,14,28
8,146,20,28
2828
3,5,14,248,141814,20,28
24,26,28
Lactase . . . . . . . . . . . . . . . . . . . . . . . . . . . .Lipase . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Microbial rennet. . . . . . . . . . . . . . . . . . . . .Naringinase . . . . . . . . . . . . . . . . . . . . . . . .Pectinase . . . . . . . . . . . . . . . . . . . . . . . . . .Pentosanase . . . . . . . . . . . . . . . . . . . . . . .Proteases . . . . . . . . . . . . . . . . . . . . . . . . . .Streptokinase-streptodornase. . . . . . . . .Uricase . . . . . . . . . . . . . . . . . . . . . . . . . . . .Organic acidsCitric acid . . . . . . . . . . . . . . . . . . . . . . . . . .Comenic acid. . . . . . . . . . . . . . . . . . . . . . .Erythorbic acid. . . . . . . . . . . . . . . . . . . . . .Gluconic acid. . . . . . . . . . . . . . . . . . . . . . .Itaconic acid. . . . . . . . . . . . . . . . . . . . . . . .2-keto-D-giuconic acid . . . . . . . . . . . . . . .~-ketoglutaric acid. . . . . . . . . . . . . . . . . . .Lactic acid . . . . . . . . . . . . . . . . . . . . . . . . .Malic acid . . . . . . . . . . . . . . . . . . . . . . . . . .Urocanic acid. . . . . . . . . . . . . . . . . . . . . . .
SolventsEthanol . . . . . . . . . . . . . . . . . . . . . . . . . . . .2,3-butanediol . . . . . . . . . . . . . . . . . . . . . .Vitamins and growth factorsGibbereliins . . . . . . . . . . . . . . . . . . . . . . . .Riboflavin . . . . . . . . . . . . . . . . . . . . . . . . . .Vitamin B12. . . . . . . . . . . . . . . . . . . . . . . . .Zearalanol. . . . . . . . . . . . . . . . . . . . . . . . . .Nucleosides and nucleotides5-ribonucieotides and nucleosides . . . . .Orotic acid . . . . . . . . . . . . . . . . . . . . . . . . .Ara-A-(9-B-D-arabino-furanosyl) . . . . . . ..6-azauridine . . . . . . . . . . . . . . . . . . . . . . . .
282017,282820,2820,2814,17,18,20,282
14,1717
4,17,181717
5
9
1,12,13131311
15
aBlankm=n~ noU.S.pr~ucer in 1977;therefore, l~produeedbyoneormore foreign flrms(fromatleast 120different firms).
SOURCE: OtticeotTechnology Assessment.
sents a major impact of genetic engineering. Toestimate this number these two calculationsmust be made:
● the value or volume of chemicals thatmight be produced by fermentation, and
● the number of production workers neededper unit volume of chemicals produced.
Any prediction of the potential volume ofchemicals is necessarily filled with uncertain-ties. The approximate market value of organicchemicals produced in the United States is givenin appendix I-B. Total U.S. sales in 1979 werecalculated to be over $42 billion. On the basis ofthe assumptions made, $522 million worth ofbulk organic chemicals could be commercially
produced by genetically engineered strains in10 years and $7.1 billion in 20 years. TableI-B-l0 in appendix I-B lists the potential marketsfor pharmaceuticals. Excluding methane pro-duction, the total potential market for productsobtained from genetically engineered orga-nisms is approximately $14.6 billion.
If the production of chemicals having thisvalue is carried out by fermentation, it impossi-ble to calculate how many workers will beneeded. Data obtained from industrial sourcesreveal that 2 to 5 workers, including those insupervision, services, and production, are re-quired for $l million worth of product. Hence,30,000 to 75,000 workers would be required forthe estimated $14.6 billion market.
Ch. 5—The Chemical lndustry ● 103
Table 19.—U.S. Fermentation Companies
Producers of Baker’s yeast and food/feed yeast inthe United States in 1977Baker’s yeast:
American Yeast Co., Baltimore, Md.Anheuser-Busch, Inc., St. Louis, Mo.Federal Yeast Co. (now Diamond Shamrock),
Baltimore, Md.Fleischmann Yeast Co., New York, N.Y.Universal Foods Corp., Milwaukee, Wis.
Food/feed yeast:Amber Laboratories, Juneau, Wis.Amoco Foods Co., Chicago, Ill.Boise-Cascade, Inc., Portland, Oreg.Diamond Mills, Inc., Cedar Rapids, IowaFleischmann Yeast Co., New York, N.Y.Lakes States Yeast Co., Rhinelander, Wis.Stauffer Chemical Co., Westport, Corm.
Enzyme producers, 1977Clinton Corn Processing Co., Clinton, lowaMiles Laboratories, Inc., Elkhart, Ind.Premier Malt Products, Inc., Milwaukee, Wis.
SOURCE: Compiled by Perlman, Arner/can Soc/ety for M/crobio/ogy News 43:2,1977, pp 82-89.
Since the chemicals considered above arecurrently being produced, any new jobs in bio-technology will displace the old ones in thechemical industry. Whether the change will re-sult in a net loss or gain in the number of jobs isdifficult to predict. However, a rough estimate
indicates that approximately the same numberof workers will be required per unit of output.
Estimates of the number of workers are di-vided into: 1) workers directly involved in the
growth of the organisms; and 2) workers in-volved in the "recovery" phase, where theorganisms are harvested and the chemical prod-uct is extracted, purified, and packaged. Basedon industry data, the number of workers in thefermentation phase is approximately 30 percentof the total, and those in recovery approximate-ly 50 percent. Hence, about 9,000 to 22,500workers might be expected to hold jobs in theimmediate fermentation area, and about 15,000to 37,500 workers would be involved in han-dling the production medium (with or withoutthe organisms).
Estimates of the number of totally new jobsthat would be created are highly speculative;they should allow for estimates of increases inthe quantity of chemicals currently being pro-duced and the production of totally new com-pounds. According to estimates by Genex, thenew and growth markets may reach $26 billionby the year 2000, which would add 52,000 to130,000 jobs to the present number.
