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~ Q _MERICA LEADS the world in the bio- sciences, thanks largely to 25 years of Major support for fundamental research by the federal government. This research in the "new" biology- aspects of which are popularly known as biotechnology is providing the basis for revolutions in health care, agriculture, food processing, environmental improvement, and natural resource utilization. The new technol- ogies that will be made possible by advances in the biosciences, and particularly in molecular biology, will be applied to the search for solu- tions to some of the world's most pressing problems. They will, in addition, create new industries and spur economic growth. Estimates of the potential annual market for new products from these technologies range from $56 billion to $69 billion for the year 2000 (Table 3.11. CHALLENGES TO CHEMICAL ENGINEERS The commercialization of developments in biotechnology will require a new breed of chem F,?~ BET, ~ ERG ~ N T CHE 4~A ~ EAN 5~.7VEE:~ .\ ical engineer, one with a solid foundation in the life sciences as well as in process engineering principles. This engineer will be able to bring innovative and economic solutions to problems in health care delivery and in the large-scale implementation of advances in molecular biology. The biologically oriented chemical engineer will focus on areas ranging from molecular and cellular biological systems (biochemical engi- neering) to organ and whole-body systems and processes (biomedical engineering). Biochemi- cal engineers will focus on the engineering problems of adapting the "new" biology to the commercial production of therapeutic, diagnos- tic, and food products. Biomedical engineers will apply the tools of chemical engineering modeling and analysis to study the function and response of organs and body systems; to elu- cidate the transport of substances in the body; and to design artificial organs, artificial tissues, and prostheses. These exciting opportunities for chemical engineers are described in more detail below, first in terms of the potential impact on TABLE 3.1 Estimated World Markets for the Products of Biotechnology (millions of dollars Year Market198519902000 Medical products Pharmaceuticals 3,50020,000-30,000 Diagnostics1001,5005,000 Veterinary products1001,5005,000 Other (materials, sensors, etc.) 75500 Chemicals Fine and specialty chemicals 5002,000-4,000 Commodity chemicals 1,000 Agricultural products Chemicals and biologicals205002,000 Plants and seeds251,5005,000-6,000 Improved animal breeds205001,000 Food and animal feed products Additives and supplements2001,5004,000 Flavors and fragrances10100500 Associated equipment and1,5004,00010,000 engineering systems TOTAL1,97515,17556,000-69,000 a Dollar values are at manufacturer's level. Inflation is estimated at 6 to 8 percent per year. SOURCE: SRI International.

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BlOTECHN0LOGY AND BlOMEDECINE society and then in terms of intellectual frontiers for research. Human Health Chemical engineers are needed to help trans- form the results of basic health research into practical products. They have been instrumental in designing processes for the safe and econom- ical production of extremely complex therapeu- tic and diagnostic agents (e.g., insulin and hepati- tis-B surface antigen). The insert boxes in this chapter on platelet storage (p. 19), tissue plas- minogen activator (p. 21), interferons (p. 29), and kidney function (p. 32) illustrate the signif- icance of chemical engineering research in this area. Artificial Organs, Artificial Tissues, and Prostheses Chemical engineers can also make an impor- tant contribution to the development of artificial organs, artificial tissues, and prostheses. In fact, lo the first successful artificial or- gan the artificial kidney was the result of an innovative NIH program in the early 1960s that brought together an interdisci- plinary team of chemical engi- neers, materials scientists, and physicians. Chemical engineers applied the fundamental con- cepts of fluid mechanics, mem- brane transport theory, mass transfer, and interracial physical chemistry to systems design. They developed predictive cor- relations relating the blood-clear- ance performance of a dialyzer to operating parameters such as membrane area, channel dimen- sions, blood and dialysate flow rates, pressure drop in the sys- tem, and temperature. Within 5 years, several soundly engi- neered prototype systems, using disposable membrane cartridges and sophisticated monitoring and control equipment, were in ad- vanced stages of development. By the mid-1970s, hemodialysis had graduated from an experimental procedure to a well-established, reliable, and safe means of sustaining patients suffering from acute and chronic renal failure. Today, hemodialysis and its companion process, hemofiltration, are stan- dard hospital and clinical procedures and are responsible for major reductions in mortality and morbidity due to kidney failure (Plate 1~. The success of the artificial kidney can be attributed to the relative simplicity of its task. Unwanted substances are removed through a membrane separation carried out in a device external to the body. Some of the targets for future artificial organs, such as the pancreas and the liver, are much more complex systems in which significant numbers of chemical reac- tions are carried out. In these cases, replace- ment might take the form of hybrid artificial organs containing living and functional cells in an artificial matrix. Development of such sys- tems will be critically dependent on the contri- butions of chemical engineers to interdisciplin- ary teams.

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20 FRONTIERS 1A/NT w<~7~.~L E.l\~.\EERING The concept of the artificial pancreas illus- diagnostic systems and devices. Molecular bi trates how chemical engineers can develop new ologists have discovered or created a variety of enzymes and monoclonal antibodies that are capable of detecting a wide range of diseases, disorders, and genetic defects. Chemical engi neers are needed to incorporate these materials into devices and systems that are fast, inexpen sive, accurate, and not susceptible to error on the part of the person carrying out the test. For example, although an enzyme-linked immuno sorbant assay (ELISA) exists for detecting the antibodies to cytomegalovirus (CMV) in blood samples, it cannot be reliably used in practice to follow the course of a new CMV infection. The error introduced into the test by having different operators perform it on each new blood sample in the series is sufficient to render highly questionable the interpretation of trends in the series, particularly if changes in the magnitude of the result are small. It is important to be able to follow trends in CMV antibodies because CMV infections can be life-threatening to in dividuals with compromised immune systems, and congenital CMV infections are the single largest cause of birth defects. Chemical engineering research leading to the design of devices and systems that are fast and "accurate" includes the following: artificial or semiartificial organs, particularly if they are grounded in whole-organ physiology and biochemistry and capable of communicating fluently with endocrinologists and physiologists. A chemical engineer working alone might con- ceive of an implantable power-driven insulin - pump, for instance, controlled by feedback from an electronic glucose sensor. In talking with an endocrinologist, the engineer might devise an implantable device containing viable pancreatic islet cells that functions as a normal pancreas. Working with a subcellular physiologist and enzymologist, the chemical engineer might come up with what is, in effect, an artificial islet cell- a "smart membrane" device that senses blood glucose levels and in response releases insulin from a reservoir encapsulated by the membrane. Each of these design concepts is potentially use- ful; the one that ultimately succeeds in practice will be the one that is easiest to make, most reliable, and most durable under the actual condi- tions of use. The wide choice of options and alter- natives makes this field of research particularly exciting and rewarding for chemical engineers. Artificial organs that perform the physical and biochemical functions of the heart, liver, pan- creas, or lung are one class of organ replace- ments. A rather different target of opportunity is the development of biological materials that play a more passive role in the body; for example, · biocompatible polymer solutions whose theological properties make them suitable as replacements for synovial fluids in joints or the aqueous and vitreous humors in the eye; · temporary systems that stimulate the re- generation of lost or diseased body mass and then are absorbed or degraded by the body (e.g., an artificial "second skin" for burn pa- tients); and · electrochemical signal transduction sys- tems that would allow the body's nervous sys- tem to communicate with and control muscu- loskeletal prostheses. Diagnostics A second area rich in opportunities for chem- ical engineers is the design and manufacture of · development of selectively adsorbent, functionalized porous media to which immu- noreagents can be affixed and that are amenable to speedy optical assay after contact with body fluids; · design of fluid-containing substrates that allow small volumes of test fluids to contact reagents efficiently and with highly reproducible assay response; and · design of flexible manufacturing systems to make the wide variety of expensive monoclonal antibodies needed for diagnostic test kits. Chemical engineers at several pharmaceutical firms are using hollow fiber reactors to grow monoclonal antibody-producing hybridomas in an in vitro batch process. Research on reactor design to optimize the production of monoclonal antibodies will have a significant impact on the future development, economy, and use of di- agnostic tests.

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BIOTECHNOLOGY AND BIOMEDICINE Preventing and Curing Disease The biological activity of many of the next generation of compounds needed to prevent disease (e.g., vaccines) or to cure it (e.g., drugs) will depend on precisely de- signed three-dimensional config- urations. These configurations can be most easily created by syn- thesizing the compounds biolog- ically or from biologically de- rived precursors, using cells that have been altered through re- combinant DNA techniques (Plate 21. The manufacture of these compounds, examples of which are listed in Table 3.2, will entail new challenges for chemical en- gineers. For processes involving bacteria or yeast as product sources, the manufacture of mol- ecules with the correct three- dimensional configuration may require additional steps to mod- ify or refold the proteins. Pro- cesses involving plant and mam- malian tissue cultures as product sources will require new types of reactors capable of growing the specialized cells, control pro- cedures and sensors tailored for biological processing, and ex- tremely special and gentle puri- fication procedures to ensure that products of adequate purity can be produced without chemical change or loss of configuration. These are formidable engineer- ing problems. Chemical engi- neers, long involved in the man- ufacture of antibiotics, peptides, and simple proteins, have signif- icant experience to apply to these problems. Providing new modes of deliv- ering drugs presents almost as important an opportunity as pro- viding new ways of making them. The standard practice of period- ically administering drug doses can lead to initial concentrations in the body that may be sufficiently high to induce undesir- able side effects. Later, as the drug is metab- olized or eliminated, its concentration can drop below the effective level (Figure 3.11. This

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22 FRONTIERS IN CHEMICAL ENGINEERING TABLE 3.2 Important Therapeutic Targets of Opportunity Therapeutic Action Antigens Interferons Tissue plasminogen activators Human growth hormone Neuroactive peptides Regulatory peptides Lymphokines Human serum albumin Gamma globulin Antihemophilic factors Monoclonal antibodies Stimulate antibody response Regulate cellular response to viral infections and cancer proliferation Stop thrombosis by dissolving blood clots Reverse hypopituitarism in children Mimic the body's pain-controlling peptides Stimulate regrowth of bone and cartilage Modulate immune reactions Treat physical trauma Prevent infections Treat hereditary bleeding disorders Provide site-specific diagnostics and drug delivery problem is particularly important with drugs that are metabolized or eliminated rapidly from the body and with drugs that have a narrow therapeutic range (the span between the thera- peutically effective and the toxic concentra- tions). The optimal pharmacological effect can sometimes be attained by establishing and main- taining a steady-state concentration of the drug or by time-sequencing its administration. The controlled release of short-half-life drugs over a long period of time can be effected by admin- istering the drug through low-flow pumps, as a mixture of capsules that disintegrate at different rates, or in pouches inserted under the eyelid o a UJ he 8 TOXIC LEVEL A A v/ /MINIMUM V / EFFECTIVE LEVEL TIME FIGURE 3.1 When a tablet of medicine is taken, or an injection given, sharp fluctuations of drug levels in the body can result. At the peak level, undesirable side effects of the drug can manifest themselves. Unless the tablet or injection is given very frequently, the level of the drug in the body can fall too low to be effective. Chemical engineers are working on ways to deliver drugs that maintain a steady, effective level of the drug in the body. or taped to the skin (Figure 3.21. Chemical engineers have been instrumental in designing and manufacturing polymers that are capable of such controlled release over long periods of time. Another approach to delivering drugs is to target the administration of a drug to a specific site in the body. This might be accomplished by coupling a drug to an antibody that has been cloned to attack a specific receptor at the disease site. This approach would make possible, for example, the selective exposure of tumor-bear- ing tissues to high concentrations of toxic drugs. Chemical engineers are needed to produce such targeted drugs and to elucidate the kinetics of monoclonal antibody transport through the body to target sites. Other areas in therapeutics that are ripe for interdisciplinary collaboration include the de- sign of special-purpose pumps and catheters, sterile implants that allow access from outside the body to veins and body organs, and imaging techniques for monitoring drug levels. Efforts by chemical engineers to provide improved data acquisition and quantitative modeling of phar- macokinetics can lead to the design of better drug administration procedures and better tim- ing to maximize the delivery of drugs to the organs that need them while minimizing the exposure of other organs. Agriculture Major opportunities exist for chemical engi- neers to help develop agricultural biochemicals.

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BIOTECHNOLOGY AND BIOMEDICINE FIGURE 3.2 This transdermal (through the skin) product delivers a steady level of nitroglycerin to the body, pre- venting the pain of angina. The thin, adhesive unit admin- isters the drug directly to the bloodstream when applied to the skin. This once-a-day patch provides medication without interfering in a patient's daily activities or without having to take pills several times a day. It does not require puncturing the skin with a needle. Chemical engineers are involved in the design and manufacture of new polymer systems for medical applications such as this. Courtesy, ALZA Corporation. These opportunities roughly parallel the fron- tiers that have opened up in the human health area. In agriculture, a deeper understanding of biological processes in plants has paved the way for biologically derived fungicides and herbicides that are highly potent, species spe- cific, and environmentally safe. The rapid in- troduction of these compounds into widespread use will require expertise in process design, process control, and separation technology to ensure that they are manufactured free from contaminants that would threaten the environ- ment or worker safety. A second focus for chemical engineers in agriculture is the improvement of veterinary pharmaceuticals (e.g., peptide hormones that promise to stimulate growth, fecundity, and feed efficiency in farm animals) and vaccines. The prospects for improvement of these com- pounds parallel the bright prospects for human ~3 pharmaceuticals and vaccines, and the require- ments for chemical engineering expertise are . ·. similar. A third focus is the development of large- scale plant-cell culture techniques. These tech- niques convert undifferentiated cell clumps into differentiated cells of genetically selected roots and stems ready for planting. Such plant cell clones are already being used to produce new crop varieties that are more resistant to adverse environmental conditions or disease. Examples include disease-resistant trees and virus-free potatoes. Cell culture techniques will continue to be used to increase crop productivity by allowing horticulturists to propagate quickly new plant strains showing ~ increased resistance to pests, drought, or soil salinity; ~ higher productivity or enhanced growth rates; · ability to produce increased amounts or higher quality of seed proteins and other plant products such as alkaloids, carotenes, latex, and steroids; and ~ improved efficiency of nitrogen fixation and photosynthesis . At present, cell culture work is done mostly by hand by horticulturists in large greenhouses (Plate 3~. Chemical engineers could greatly in- crease the usefulness of this method of plant propagation by developing efficient automated processes for producing plants from cloned cells. Biochemical Synthesis By manipulating the genetic machinery of the cell, it is possible to cause most cellular systems to produce virtually any biochemical material. Unfortunately, the growth of cellular systems (particularly in tissue cultures) is constrained by end-product inhibition and repression; hence, it is difficult to produce end products in high concentration. Furthermore, cells are always grown in aqueous solution, so biochemicals produced by cellular routes must have intrinsi- cally high value in order for the cost of recovery from dilute aqueous solution to be minimized. Thus, most biochemicals of commercial interest

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,1~! to be produced by biotechnology will be high-value products such as enzymes, biopolymers, or metabolic cofactors. In general, their potency is so high that only small quantities will be needed. Accordingly, the challenge to chemical engineers in producing these products is not so much in process scale-up but rather in obtaining high process yield and minimal process losses. Enzymes are an important class of biochemicals; they are the ca- talysts needed in the chemical reaction cycles of living systems, and they execute their catalytic role with exquisite chemical pre- cision. Enzymes have great po- tential in synthetic chemistry be- cause they can effect ster- eospecific reactions, avoiding the production of an unwanted iso- mer of a complex molecule. Cur- rently, many of the enzymes used in industrial processing (e.g., those used to convert starch into sugar or milk into cheese) are derived from microbial sources because they are beyond the practical reach of current syn- thetic chemical technology. Bio- technology offers the potential, through cellular genetic control, for making enzymes not only those that are now used industrially but also others for new uses in synthetic chemistry. The synthesis and processing of these complex mol- ecules require conditions that will maintain their specific three-dimensional structures. One chal- lenge for chemical engineers will be to develop processes that can meet the rigorous require- ments for optimally producing and recovering enzymes. Another challenge will be to understand the chemical transformations that enzymes cata- lyze. The goal would be to determine how these transformations can be used or tailored through changes in enzyme structure to produce com- pounds that are difficult or costly to produce -rim ~7A\I {~ - ~,;'~. 2 ~ ~1\'v'G:~R i^~.= by traditional synthetic chemistry. Addressing this challenge will bring the chemical engineer into close contact with biochemists and syn- thetic chemists. Environment and Natural Resources Biotechnology offers promise for improving the quality of our environment through the intro- duction of new microbial and enzymatic tech- niques for removing and destroying toxic pollu- tants in municipal and industrial wastes. This opportunity is discussed in detail in Chapter 7. The depletion of domestic high-grade ore deposits has made the United States vulnerable

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BIO~,33~ A~ ~5~,p,~r~ to shortages of metals (e.g., chromium, man- ganese, and niobium) that are important to the production of high-strength steel and other al- loys. Biological systems with a high affinity for metals are known, and genetically engineered microorganisms might be used to sequester metals from highly dilute waste streams (see Chapter 6), from dilute sources underground (see Chapter 6), or from the sea. To make such recovery concepts practical, chemical engi- neering will be needed to design systems that allow these microorganisms to function opti- mally and to efficiently contact large volumes of dilute solutions, or, in the case of in-situ metals extraction, to operate efficiently when the earth itself is the bio- reactor. Another opportunity for bio- technology may be to provide a new source for certain petro- chemicals. Biological routes to a number of organic chemicals cur- rently derived from petroleum have been demonstrated (Table 3.31. For structurally complex chemicals, these routes may prove more economically effi- cient than alternative routes (e.g., those using synthesis gas from coal gasification as a starting ma- terial). Whether this will be the case depends largely on engi- neering research efforts in bio- processing and in other resource areas. INTERNATIONAL COMPETITION Who will lead the commer- cialization of the "new" biol- ogy? The answer is not yet clear. Our principal technological com- petitors in the world, the Euro- peans and the Japanese, are ag- gressively expanding their efforts to commercialize the results of basic biological research. West Germany, Japan, and the United Kingdom each have three large government-supported institutes dedicated to biotechnology. The United States has only one center of comparable magnitude (the MIT Bio- technology Process Center). Not surprisingly, our competitors are establishing commercial positions by practicing effective and forward- looking biochemical and biomedical engineer- ing. Some examples of their recent accomplish- ments attest to their aggressiveness. ~ Basic technology for membrane separation of biomolecules was invented in the United States, but the West Germans and the Japanese lead in its application to separations of enzymes and amino acids from complex mixtures. Jap

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26 TABLE 3.3 Potential Routes to Commodity Chemicals by Microbial Fermentation of Glucose Chemical Microorganism(s) Ethanol Butanol Adipic acid Methyl ethyl ketone Glycerol Citric acid Saccharomyces cerevisiae Zymomonas mobilis Clostridium acetobutylicum Pseudomonas species Klebsiella pneumonias Saccharomyces cerevisiae Dunaliella species Aspergillus niger SOURCE: T. K. Ng, R. M. Busche, C. C. McDonald, and R. W. F. Hardy, Science, 219, 1983, 733. Copyright 1983 by the AAAS. Excerpted with permission. anese government support of membrane sepa- ration research and development alone amounted to $21 million in 1983. This is many times the level of comparable effort expended by the U.S. government. One impact of the well-funded Japanese effort can be seen in the increasing number of Japanese kidney dialyzers appearing in U.S. hospitals. · Technology for very large (400,000-gallon) continuous fermenters was developed and is being practiced in the United Kingdom. This development pushes biochemical engineering to limits not yet explored in the United States. · Although the use of fermentation to pro- duce ethanol is an ancient technology, more efficient immobilized-cell, continuous processes have been conceived, and Japan has established the first demonstration-scale plant. According to the Office of Technology As- sessment (OTA), Western Europe and Japan have historically maintained a large and stable funding pattern for biochemical engineering. This is not so for the United States. The existing base of biochemical engineers in other coun- tries, and their strong interest in exploiting the discoveries of the "new" biology, are reflected by extensive government funding and facilities support. It is clear that countries such as West Germany and Japan are laying a foundation of engineering research and training as part of their overall strategy for intense international com ~OlYTIEJ~S I^~Y CHEMICAL EIVOlIVEERIAi46; petition in biotechnology and medicine. The potential economic rewards for success are very great, as shown in Table 3.1. First entry into these markets will be critically important in international competition, and major shares in the worldwide bioproducts market will be cap- tured by those countries who possess the needed research infrastructure. INTELLECTUAL FRONTIERS The intellectual frontiers for chemical engi- neers in biotechnology and biomedicine can be described on a continuum from microscale through mesocale to macroscale. At either end of this spectrum are highly interdisciplinary research topics that will require modeling and analytical tools currently used by chemical en- gineers in other contexts. The important me- soscale challenges of bioprocessing will require chemical engineering expertise in reaction en- gineering, process design and control, and sep- arations. The following sections discuss these challenges in greater detail. Models for Fundamental Biological Interactions The living microbial, animal, or plant cell can be viewed as a chemical plant of microscopic size. It can extract raw materials from its environment and use them to replicate itself as well as to synthesize myriad valuable products that can be stored in the cell or excreted. This microscopic chemical plant contains its own power station, which operates with admirably high efficiency. It also contains its own sophis- ticated control system, which maintains appro- priate balances of mass and energy fluxes through the links of its internal reaction network. Cell membranes are not simply passive con- tainers for the cell's contents. Rather, they are highly organized, dynamic, and structurally complex biological systems that regulate the transfer of specific chemicals through the cell wall. One important constituent of cell membranes is a class of molecules the phospholipids- that spontaneously form two-layer films in a

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BIOTECHNOLOGY AND BIOMEDICINE number of geometries. Many of the important physical properties of cell membranes, such as two-dimensional diffusion and differentiation between the inside and the outside of a tube or sphere, can be studied with these spontaneously formed structures. If we can develop accurate quantitative models that simulate how cells respond to various environmental changes, we can better utilize the chemical synthesis capabilities of cells. Steps toward this goal are being taken. Models of the common gut bacterium Escherichia cold have been developed from mechanisms of sub- cellular processes discovered or postulated by molecular biologists. These models have pro- gressed to the point where they can be used with experiments to discriminate among pos- tulated mechanisms for control of subcellular processes. Some of the most promising potential appli- cations of biotechnology involve animal or plant cells. Models for these organisms, which have greater internal complexity as well as more demanding environmental requirements than simple cells, are not yet available. It will prob- ably be necessary to incorporate the structure of functional subunits of the cell (organelles) into models for complex cells in addition to the chemical structure that is used in bacterial cell models. Cellular reactions are subject to the limitations imposed by the laws of thermody- namics, by diffusion, and by reaction kinetics. Chemical engineers are familiar with the tech- niques for designing mathematical models that involve these parameters and should be able to make major contributions to the development of cellular models. The development of reliable models hinges on acquiring accurate data bases on enzymes, biologically important proteins, and cellular systems. The data should include physical properties, transport properties, chem- ical properties, and reaction rate information. Biological Surfaces and Interfaces Many biological reactions and processes oc- cur at phase boundaries and are thus controlled by surface interactions. Examples include such highly efficient processes as selective transport 27 of ions across membranes, antibody-antigen interactions, cellular protein synthesis, and nerve impulse transmission. Progress in achieving . . ^- · · · · . slm1 ar eInclencles in engineered enzyme pro- cesses, bioseparations, and information trans- mission can be aided by acquiring more sophis- ticated knowledge of biochemical processes at interfaces. With this knowledge, such products as synthetic antibodies for human and animal antigens, or synthetic membranes that can serve as artificial red blood cells or transport barriers, could be developed. Surface interactions play an important role in the ability of certain animal cells to grow and produce the desired bioproducts. An under- standing of the dynamics of cell surface inter- actions in these "anchorage-dependent" cells (cells that function well only when attached to a surface) will be needed, for example, to improve the design of bioreactors for growing animal cells. Interactions at surfaces and interfaces also play an essential role in the design and function of clinical implants and biomedical devices. With a few recent exceptions, implants do not attach well to tissue, and the resulting mobility of the tissue-implant interface encourages chronic inflammation. The result can be a gathering of platelets at the site, leading to a blood clot or to the formation of a fibrous capsule, or scar, around the implant (Figure 3.31. A number of fundamental questions about biological changes at the tissue-implant interface challenge chemical engineers in the design of medical implants and devices. How do cells interact with the surfaces of well-characterized materials? Which receptor sites on cell mem- branes interact with which functional groups on the surfaces of biomedical materials? What is the effect of other morphological features of the surface, or of the mechanical properties of the material? How does the metabolic activity of the cell change after a reaction with a material interface? What new enzymes or chemicals are produced by the cell after such a reaction? How does information gained in this area lead to better materials, or to the development of new methods for attaching biomedical materials to tissues? How can chemical engineers contribute

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28 to better ways of monitoring im- planted materials noninvasively? Bioprocessing Three major intellectual fron- tiers for chemical engineers in bioprocessing are the design of bioreactors for the culture of plant and animal cells, the develop- ment of control systems along with the needed biosensors and analytical instruments, and the development of processes for separating and purifying prod- ucts. A critical component in each of these three research areas is the need to relate the micro- scale to the mesoscale. Bioreactors for Manufacturing Processes Much of the early work in applying recombinant DNA technology to the production of bioactive substances has used microbial cell species such as bacteria, yeasts, and molds. These microbes are fairly easy to manipulate genetically and are hardy under adverse con- ditions. Unfortunately, animal or plant proteins produced by clones of microbial cells often lack the critical three-dimensional structure that is formed when the same proteins are produced by animal and plant cells. For this reason, these proteins may not be biologically active even though they have the correct sequence of amino acids. One important future area of biotechnol- ogy lies in using plant and animal cells in place of microbial cells. The large-scale use of plant and animal cells in tissue culture raises impor- tant problems in the design and operation of bioreactors (Plate 44. One problem mentioned earlier is that certain animal cells are anchorage-dependent. Also, plant and animal cells are easily ruptured by mechanical shear. Bioreactors for handling such cells must be designed so that the contents of the reactor can be mixed without disrupting the cells. A similar problem exists in the design of FRONTIERS IN CHEMICAL ENGINEERING ,,, ,,,.,,, ,, -~ . ,, ,.',. ~,,,T,, , ~,~,,.,,,,,,,,~, FIGURE 3.3 Implanted materials and devices in the body that are perceived as foreign objects will encourage the formation of scar tissue surrounding them. In this photomicrograph, a nonporous membrane (G), implanted between the skin and some subcutaneous tissue (D and PC), generates the synthesis of granulation tissue (GT) and a fibrotic sac (scar tissue, FS) within 4 weeks. Courtesy, Ioannis Yannas, Massachusetts Institute of Technology. systems to transfer the cells from one vessel to another. Plant cells tend to aggregate, and large ag- gregates pose problems in maintaining a supply of nutrients to all cells and in removing wastes. The development of bioreactors for plant cells will require an understanding of limitations on mass transfer in such aggregates. Some bioreactor systems must be completely protected from microbial contamination, mean- ing that not a single alien bacterium or virus particle can be allowed to penetrate the system. Reliable and economical systems need to be developed to achieve this level of contamination prevention. Along with the need for prevention is the need to be able to detect contamination at a level of a few microorganisms in a hundred kiloliters of medium. This degree of detection is not yet achievable. Research could vastly improve the crude detection methods that are used today. Most industrial bioprocesses are now oper- ated in a batch mode. Batch processing is the method of choice for small-scale production,

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BIOTECHNOLOGY AND BILE and it has the advantage that the equipment can be used for intermittent production of more than one product. An intriguing future possibility is that chemicals and biochemicals will be pro- duced by biotechnology on a large-scale, con- tinuous basis. Continuous processing frequently offers advantages in economy and uniformity of product quality. However, the engineering problems involved in converting from batch to continuous biological processing are not trivial. Continuous processing of biological systems places stringent demands on equipment design, instrumentation, and operation for maintaining aseptic conditions and biological containment. One indication of these difficulties is the fact that although processes for fermenting natural materials to produce beer predate written his 29 tory, beer is still brewed and aged in batches. Attempts to use a continuous process to manufac- ture a product as well understood as beer have not produced a beverage with acceptable taste. Process Monitoring and Control Continuous and detailed knowl- edge of process conditions is nec- essary for the control and opti- mization of bioprocessing oper- ations. Because of containment and contamination problems, this knowledge must often be ob- tained without sampling the process stream. At present, con- ditions such as temperature, pressure, and acidity (pH) can be measured rapidly and accu- rately. It is more difficult to mon- itor the concentrations of the chemical species in the reaction medium, to say nothing of mon- itoring the cell density and intra- cellular concentrations of hun- dreds of compounds. The development of rapid, accurate, and noninvasive on- line measurement sensors and instruments is a high-priority goal in the commercialization of biotech- nology (Figure 3.41. Some of these instruments will build on analytical methods now used in catalysis and other surface sciences, such as Fourier transform infrared spectroscopy, fluorospectrometry, mass spectrometry, ~ nuclear magnetic resonance (NMR) spec- trometry, and ~ combinations of some of the above-men- tioned methods with chromatography. These methods will be applied by chemical engineers to monitor and control reaction and recovery systems.

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30 >- ~ FIGURE 3.4 Several approaches to developing analytical instrumentation for bioreactors are shown in this figure. (1) Gases being fed to the bioreactor must be analyzed to determine their flow rate and composition. Flow rates can be measured with mass flowmeters or rotameters; the concentrations of oxygen and carbon dioxide in the gas mixture can be determined by electrochemical methods or IR analysis, respectively. These data, when combined with similar measurements on the gases exiting from the bio- reactor (2), provide information on oxygen uptake and carbon dioxide evolution in the bioreactor. (3) Vanous sensors may be placed in the bioreactor. Properties that might be measured include temperature, pressure, pH, dissolved oxygen, and liquid feed rates. Sensors are under development to measure glucose, ethanol, various ions (e.g., NH4, Mg2+, K+, Na+, Cu2+, and PO43-), and other important biomolecules (e.g., ATE, ADP, AMP, DNA, RNA, and NADH). (4) The rotating shaft of the impeller can be used to measure viscosity. (5) Varous spectropho- tometr~c cells can be used to measure properties such as turbidity, if the culture medium in the bioreactor is not too dense. From L. E. Erickson and G. Stephanopoulos, "Biological Reactors," ch. 12 in Chemical Reaction and Reactor Engineering, J. J. Carberry and A. Varma (eds.), Marcel Dekker, Inc., New York, 1986. Separation of Bioproducts Cell culture bioreactors produce a dilute mix- ture of cells in an aqueous medium. Recovery of the product proteins from these cells may require disruption of the cells. This creates a host of problems. Cell walls and organelles must be removed. Proteins must be concentrated from a highly dilute solution that is mostly composed of water and other small molecules. The desired proteins must be separated from other macromolecules with similar physical properties. For biologically active proteins, sep- arations must not only be specific for the target proteins, but also gentle enough to prevent denaturation and loss of biological activity and suitable for large-scale operation. Solving these FROlVTIERS I.\ CHEMICAL ElY70ilVEL~l^~'G problems requires generic research on highly selective separations, as well as on the problems of concentrating materials from very dilute so- lutions (Figure 3.51. These and other generic research opportunities in separations have been described in detail in a recent report from the National Research Council.' Pursuing these op- portunities will result in a better understanding of separation processes now used for the large- scale purification of proteins (e.g., precipitation and process chromatography). It may also result in novel separations involving aspects of tech- niques such as · chromatography, · membrane separation, · fractionation in electric and gravitational fields, · immunoadsorption, · extraction with supercritical fluids, · two-phase aqueous solution extraction, and · separation by use of microemulsions. The development of such new separations is crucial to the development of industrial bio- technology. Another approach to separation problems lies in the development of modified organisms that produce the target proteins in high yield and concentration, thus reducing the time and cost of separating the proteins from large amounts of water. This is an area where early involve- ment of chemical engineers in designing genet- ically engineered organisms would be valuable. With their insights into the requirements of downstream processing of biologically synthe- sized substances, chemical engineers could be valuable members of an interdisciplinary team of molecular biologists and biochemists seeking to tailor the genetic code of cells. Engineering Analysis of Complex Biological Systems The development of new therapeutic proce- dures will be aided by a better understanding of physiological and pathological processes in the body. One area to which chemical engineers can contribute is the application of engineering analysis to systems found in the body. The

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BIOTECHNOLOGY AND Bl0MEDICINE . FIGURE 3.5 The desired product, usually a protein, produced by a genetically engineered microorganism must be separated and purified before use. The centrifuges shown here separate the components of the microorganisms, and then further separation is carried out to isolate the one protein that is desired from the thousands of other proteins produced by the microorganism. The isolated protein must be rigorously purified to eliminate contaminants from the final product. In many cases, separation and purification is the most expensive part of the production process. Courtesy, Genentech. study of the transport of substances across membranes is an example. There is considerable knowledge of the transport of small molecules across living membranes; this should be ex- tended to studies of larger molecules. A more complete understanding of the transport of bio- logically active agents would be particularly important in diagnosis and therapy. Biochemical processes in humans can now be measured by such techniques as positron emission tomography, magnetic resonance im- aging, and x-ray computer-assisted tomography, and the measurements can be enhanced by digital subtraction methods. Chemical engineers can help elucidate the data obtained by such techniques by developing quantitative models that incorporate thermodynamics, transport phenomena, fluid mechanics, and principles of chemical reaction engineering. These ad- vances will lead to improved therapeutic pro- cedures. The normal growth of tissues and organs is under a remarkable degree of natural control. When this is compromised by genetic or mu 3) tagenic alterations, pathological processes such as birth defects or cancer can result. We need a better basic understanding of this control process. Theoretical and systematic advances by chemical engineers in process control may be applicable to the study of this problem. While the mechanical per- formance of artificial materials in the human body can be pre- dicted with some reliability, forecasting their biological per- formance is difficult. The prob- lem of interactions at surfaces has already been mentioned. Research frontiers also include developing ways to simulate in vivo processes in vitro and ex- tending the power and applic- ability of such simulations to allow for better prediction of the performance of biomedical materials and devices in the pa- tient. Fundamental information on the correlation between the in vivo and in vitro responses is limited. Chemical engineers might also make contributions to the problem of noninvasive monitoring of implanted mate- rials. IMPLICATIONS OF RESEARCH FRONTIERS The most successful efforts on problems such as those listed above will come from a new breed of chemical engineer, fluent in the lan- guage and concepts of modern biology and medicine. Currently, few chemical engineers are sufficiently knowledgeable in the principles of modern molecular biology, microbiology, genetics, and biochemistry to permit their ef- fective collaboration with life scientists. Con- versely, few life scientists are sufficiently aware of the engineering principles and practical prob- lems associated with the scale-up of biological processes, the large-scale processing of bio- products, or the development of artificial bio- logical devices. All the participating disciplines

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32 must recognize the importance of the innovative synthesis of new concepts that unite life sci- ence theory and fact with engi- neering principles, or that com- bine an engineering idea with a biological speculation. Such in- novative synthesis is likely to come about only in an environ- ment where research needs and unsolved problems can be iden- tified that bridge disciplinary boundaries and compel represen- tatives of all relevant disciplines to work together to find the best solutions. Prompt and effective exploitation of the "new" biol- ogy is dependent on the improve- ment of this disciplinary inter- face; and this is one of the most critical problems confronting bioengineering today. The need to develop a new fusion with modern biology has important implications for chem- ical engineering education and research: · The development of fruitful education and research programs in biochemical and biomedical engineering cannot take place in isolation from the life sciences; strong, complementary academic programs in the biological or medical sciences are essential. Institutions that do not have strong research activities in the life sciences should probably hot be encouraged to develop programs in biochemical or biomedical engineering. · Curricula at the undergraduate and gradu- ate levels need to be modified so that students will gain sufficient knowledge of the biological sciences to apply engineering methods of anal- ysis and design to solve problems that originate in the biological sciences. Chapter 10 discusses general principles for modifying the undergrad- uate curriculum to respond to emerging appli- cations for chemical engineering. At the grad- uate level, in-depth courses in molecular biology, biochemistry, and cellular and mammalian ^~1~&'-~5 i.\ I E.~2iNE=~N'~ physiology should be part of the course require- ments for chemical engineers specializing in bioengineering. Such courses should be struc- tured specifically for engineers, include mean- ingful laboratory experience, and provide the prerequisite background for the engineering stu- dent to take advanced biology and medical science courses, if desired. ~ Ph.D. students must be prepared for the interdisciplinary environment in which they will likely spend their careers as biochemical or biomedical engineers. The best way to do this is to expose them to interdisciplinary research as graduate students. To facilitate this, a broad and stable base of research support targeted at interdisciplinary research must be created. Par- ticularly valuable would be support targeted to

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If r REV ~ ,~ Id medium-sized research collaborations bringing together two or three co-principal investigators whose backgrounds and expertise cross the boundary between chemical engineering and the life sciences, including medicine. (See "Cross- disciplinary partnership awards" in Chapter 10.) While large centers certainly can provide an interdisciplinary research environment, a greater number of medium-sized collaborations might foster a faster growth of U.S. capabilities in critical bioengineering areas. · A faculty expert in both the engineering and the biological aspects of the research fron- tiers described in this chapter is needed to mount a significant educational program in biochemical and biomedical engineering. The hiring of fac- ulty into chemical engineering departments whose 3: training is initially in the medical and life sciences is one step that might be encouraged. The pres- ence of a strong research biology department or a nearby teaching hospital/medical school is prob- ably needed to furnish an envi- ronment that will attract and re- tain the best such faculty. There are many practical obstacles to be overcome in making such ap- pointments successful. A pro- gram to encourage "pioneers" who wish to cross the disciplin- ary divide into chemical engi- neering departments is outlined in Chapter 10. Some bioengi- neering departments have al- ready made joint appointments with biological and medical fa- culties. Where the organizational problems inherent in such ar- rangements can be avoided or resolved, such appointments should be encouraged. A number of other factors will be important in sustaining a vital research effort in biochemical and biomedical engineering. These include: ~ Instrumentation and facili- ties. Suitable instrumentation and facilities for education and research in bioen- gineering can be very expensive. For example, equipping a state-of-the-art tissue-culture facil- ity for engineering studies costs in the range of $500,000. Other costly equipment required in- cludes ultracentrifuges, electron microscopes, mass spectrometers, NMR spectrometers, scin- tillation counters, and specialized instruments to study surfaces (see Chapter 91. Some of this equipment must be specially modified and ded- icated to a particular group's use. Other instru- ments can be shared among a coterie of chemical engineering, biological, and medical research- ers. Chemical engineers should make use of existing facilities in life sciences and medical departments wherever possible, particularly in the case of animal facilities.

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34 National research centers. Special, highly sophisticated ensembles of analytical and com- putational equipment and expertise might be brought together in national research facilities available to academic, government, and indus- trial groups for limited time periods. Some potential areas of specialization for such centers include modeling and control of bioreactors, measuring and modeling pharmacokinetic data, measuring actual and simulated bioflows in living systems and reactors, and studying ki- netics of biological reactions and related pro- cesses. · Effective coupling to industry. Effective links between universities and industry are es- sential to successful research and education in biochemical and biomedical engineering. In this rapidly growing technological area, a particular need is effective contact and interchange be- tween chemical engineering departments and smaller venture-capital firms specializing in bio- technology or biomedical products. Liaison pro- grams and other mechanisms that promote in- teractions between active researchers, and opportunities for students to spend time in industrial laboratories, should be encouraged. · Better communication among professional societies. The field of biochemical and biomed- ical engineering is in danger of fragmentation among a plethora of professional societies, some of which are quite narrow in focus. Literally dozens of such organizations are currently on the scene. The AIChE could play a valuable role in ameliorating this situation by promoting better communication and cooperation among societies and researchers in other disciplines. The biochemical and biomedical engineers of the future will be in great demand by industry, academia, and federal and state government agencies. Already, there is a strong demand by universities for faculty in biochemical and biomedical engineering. While recent demand ~. . . . . . . . .. . from industry has not been as intense, lit IS projected to increase strongly as products are better defined and move closer to commercial production.' Federal and state agencies that will be responsible for regulating the introduction of new bioproducts into society are woefully FRONTIERS IN CHEMICAL ENGINEERING understaffed in biologically conversant engi- neers. These agencies (e.g., EPA, USDA, and FDA) should also support chemical engineering research to obtain the data, models, and insight necessary for effective risk assessment and management. It is characteristic of U.S. labor markets for scientific and engineering personnel to experi- ence severe shortages and overcompensating excesses. Now is the time for the federal gov- ernment and universities to build a research and education base in academia that can respond flexibly and efficiently to the personnel demands that will inevitably come. Now is the time to prepare a cadre of chemical engineers who will interact as easily and successfully with life scientists as chemical engineers currently do with chemists and physicists. NOTES 1. National Research Council, Committee on Sepa- ration Science and Technology. Separation and Purification: Critical Needs and Opportunities. Washington, D.C.: National Academy Press, 1987. 2. U.S. Congress, Office of Technology Assessment. Commercializing Biotechnology An Interna- tional Analysis. Washington, D.C.: U. S. Govern- ment Printing Office, 1983. SUGGESTED READING J. Feder and W. R. Tolbert. "The Large-Scale Cultivation of Mammalian Cells.'' Sci. Am., 248 (1), January 1983, 36. E. L. Gaden, Jr. "Production Methods in Industrial Microbiology." Sci. Am., 245 (3), September 1981, 180. A. E. Humphrey. "Commercializing Biotechnology: Challenge to the Chemical Engineer.'' Chem. Eng. Prog., 80 (12), December 1984, 7. A. S. Michaels. "Adapting Modern Biology to In- dustrial Practice." Chem. Eng. Prog., 80 (6), June 1984, 19. A. S. Michaels. "The Impact of Genetic Engineer- ing." Chem. Eng. Prog., 80 (4), April 1984, 9. National Academy of Sciences-National Academy of Engineering-Institute of Medicine, Committee on Science, Engineering, and Public Policy. "Report of the Research Briefing Panel on Chemical and Process Engineering for Biotechnology," in Re- search Briefings 1984. Washington, D.C.: National Academy Press, 1984.

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BIOTECHNOLOGY AND BIOMEDICINE National Research Council, Engineering Research Board. "Bioengineering Systems Research in the United States: An Overview," in Directions in Engineering Research. Washington, D.C.: Na- tional Academy Press, 1987. National Research Council, National Materials Ad 35 visory Board. Bioprocessing for the Energy-Effi- cient Production of Chemicals. Washington, D.C.: National Academy Press, 1986. R. A. Weinberg. "The Molecules of Life." Sci. Am., 253 (4), October 1985, 48.

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