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Chemical Engineering Focuses Increasingly on the Biological • Field of biomolecular engineering emerges at the interface between chemical engineering and the life sciences
produced. This diversity can have a substantial impact on the efficacy of recombinant glycoproteins used in human therapeutics, such as tissue plasminogen activator and erythropoietin. C h e m i c a l e n g i n e e r i n g professor Charles F. Goochee of Stanford University exemplifies the new breed of chemical engineers studying such phenomena. "Oligosaccharides can affect Stu Borman, C&EN Washington many glycoprotein properties," says Goochee. "Therefore, it's important for ince the beginnings of chemical us to try to understand the . . . factors engineering in the late 19th centhat d e t e r m i n e glycoform distributury, traditional concerns of the tion." field have focused on areas such as petroleum refining and production of inThe effect of cell environment on dustrial chemicals, plastics, and such the glycosylation pattern of proteins consumer products as synthetic deterproduced in cells was recently probed gents. Most chemical engineers still in a study by Goochee and chemical work in these areas today. engineering graduate student Timothy J. Hahn. "Hahn is now at Merck & But in the past 15 to 20 years chemiC o / s manufacturing division in West cal engineering has increasingly develPoint, Pa., w h e r e he's involved in oped a life sciences orientation as well. Merck's efforts to make viral vacThis biological side of chemical engineering was underscored in December cines- - a n example of the biological fields chemical engineers are at a meeting in W a s h i n g t o n , getting quite involved in," says D.C., on "Research OpportuniGoochee. ties in Biomolecular Engineering: The Interface between Chemical In the study, Hahn and GooEngineering and Biology/' chee found that as human liver The meeting was sponsored cells progress from a rapidly diby the National Institute of Genviding state to a slowly dividing eral Medical Sciences (NIGMS), or no-growth state, the glycoa unit of the National Institutes sylation process changes. The of Health, a n d cochaired by glycoprotein transferrin secreted chemical engineering professor from slowly dividing cells conGeorge S. Georgiou of the Unitains four to five times more biversity of Texas, Austin, and a n t e n n a r y (doubly branched) health sciences a d m i n i s t r a t o r oligosaccharides than transferrin Irene B. Glowinski of NIGMS. secreted by rapidly dividing The purpose of the meeting, says cells. This change correlates with Glowinski, was "to highlight the a decrease in the intracellular acresearch opportunities and scitivity of a glycosyltransferase entific impact that can be made that catalyzes biosynthesis of the by biomolecular engineering, to oligosaccharides. "This is the demonstrate its relevance to the Model of membrane-bound glycoprotein Thy-1 shows first demonstration of a growthmission of the institutes, and to large size of carbohydrate moieties (yellow and red), associated change in glycosylaincluding carbohydrate structure (red) that helps anchor promote interactions between tion," says Goochee. glycoprotein to cell membrane (green). Protein part of the biochemical engineering and molecule is blue. Chemical engineers are studying the Another major part of biomolife science communities." factors that influence the wide structural diversity of lecular engineering is metabolic engineering, the modification The chemical engineers who such glycoproteins
S
26
JANUARY 11, 1993 C&EN
attended the NIGMS meeting are a group that is more dedicated to recombinant proteins than to petroleum distillation, more interested in redirecting metabolism than in fluid mechanics, more fascinated with bioseparations than with unit operations, more concerned with biocatalysis than with zeolites, and more intrigued with cell and tissue engineering than with injection molding. In short, they represent a subset of chemical engineers who have become more—well, biocompatible. A case in point is some of the chemical engineering research currently being done on production of recombinant proteins—the engineering of cells to generate products of pharmacological and technological importance. Many recombinant proteins are glycoproteins—protein and carbohydrate copolymers. Random events in the biosynthesis of glycoproteins lead to tremendous diversity in the number of glycoforms (oligosaccharide variants)
of the metabolism of organisms to produce useful products. MicrobioloWaste-to-ethanol process uses engineered organisms gist Lonnie O. Ingram of the UniversiBiomass or ty of Florida, Gainesville, is working waste materials at the interface between chemical engineering and biology to modify bacteria for production of ethanol. Physical pretreatment (chopping & grinding) The Clean Air Act amendments of 1990 mandate the use of oxygenates such as ethanol in automotive fuels. Ethanol is currently produced by yeast Treatment with dilute acid fermentation of cornstarch-derived for hydrolysis of hemicellulose sugar. But because of the high cost of Cellulose and Cellulase corn, ethanol is expensive. lignin solids enzymes Microorganisms that can produce ethanol from woody waste materials \ Genetically could potentially lower its cost. But Enzymatic hydrolysis C09 C0 0 engineered & fermentation known microorganisms cannot effiethanolciently ferment all the sugars in celluproducing microorganisms lose and hemicellulose, the major constituents of plant cell walls. Ingram and coworkers cloned and Dilute ethanol sequenced two bacterial genes that enCombustion to Solids code enzymes for converting pyruvate Distillation produce energy for running plant into ethanol, and used them to redirect the central metabolism of Klebsiella oxy95% Ethanol toca, Escherichia coli, and other bacteria to produce ethanol. The engineered Dehydration bacteria efficiently ferment all of the 100% Ethanol pentose and hexose sugars derived from cellulose and hemicellulose. The researchers also engineered these organisms to produce additional cellulase enzymes for depolymerization of cellulose. Recombinant bacteria ferment biomass- and waste-derived sugars to ethanol, The genetically engineered bacteria and also provide additional cellulase enzymes used to depolymerize cellulose make possible the conversion to ethSource: Lonnie O. Ingram, University of Florida anol of a wide range of organic waste materials—including wood, grass, and other biomass; the biodegradable part of municipal solid waste; and waste be broken down by cellulase enzymes, screening mutant bacteria for imstreams from food, dairy, and pulp and both from the engineered organisms proved strains. However, it is now pospaper processing. The 90 to 95% effi- and from fungal sources. The resulting sible using recombinant DNA technolciency of the new technology and its fermentable sugars will then be fer- ogy to manipulate the biosynthetic use of waste material as a feedstock mented to ethanol by the engineered pathways of microorganisms to further will allow ethanol to be produced at bacteria. improve their productivity or to alter lower cost than with conventional Also using recombinant DNA tech- the product produced. corn-based technology, according to nology, chemical engineers Li-Hong Malmberg, Hu, and Sherman develthe company commercializing it— Malmberg and Wei-Shou Hu and mi- oped a kinetic model for a biosynthetBioEnergy International, of Gainesville, crobiologist David H. Sherman of the ic pathway in the bacterium StreptoFla. BioEnergy believes that low-cost University of Minnesota have achieved myces clavitligerus that produces ethanol has tremendous market poten- dramatic success in increasing the pro- O-carbamoyldeacetyl cephalosporin C tial as a cleaner burning replacement duction of drug precursors in antibiot- and cephamycin C, starting materials for gasoline. ic-producing microorganisms. for several semisynthetic (3-lactam anA patent for the engineered bacteria The (3-lactam antibiotics, including tibiotics. The model showed that the was issued in 1991 to the University of the penicillins, cephalosporins, and flux of a-aminoadipic acid plays a key Florida—U.S. patent number 5,000,000, cephamycins, "are among the most role in controlling the rate of cephcoincidentally. BioEnergy has licensed important antimicrobial agents ever alosporin biosynthesis. the patent and is planning to build developed," says Sherman. Since their They therefore cloned a copy of the three large waste-to-ethanol plants. In discovery, the productivity of micro- gene for lysine ^-aminotransferase, a the plants, hemicellulose will be broken organisms used to make these drugs key enzyme in the biosynthesis of down with dilute acid. Cellulose will has been greatly increased, largely by a-aminoadipic acid, and inserted it
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JANUARY 11, 1993 C&EN
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SCIENCE/TECHNOLOGY
into S. clavuligerus. The recombinant strain produces O-carbamoyldeacetyl cephalosporin C and cephamycin C at levels 100% higher than in the wildtype strain. This is a significant achievement in that the highest previous increase in cephalosporin production levels by recombinant means was about 16%, says Sherman. Molecular bioseparations is perhaps the subdiscipline of biomolecular engineering that is closest philosophically to the process separations work that chemical engineers have been traditionally associated with. "All of us who think about purifying proteins, and particularly the proteins that might be used as biopharmaceuticals, need to think about how to produce very pure, very active, very homogeneous proteins on a large scale, and that requires the input and expertise that the engineering perspective brings," says Richard R. Burgess of the McCardel Laboratory for Cancer Research at the University of Wisconsin, Madison. Chemical engineering professor
Richard C. Willson of the University of Houston points out that "chemical engineers have been interested in separations since day one, ... but until the advent of the biotechnology industry they didn't work on proteins.... When the need for isolation of proteins . . . emerged, only a few . . . visionary chemical engineers were prepared. . . . Mistakes were made, basic vocabulary and basic techniques had to be learned. Some fairly embarrassing stories circulate around from those days." However, says Willson, "there is now a sea change in the nature of chemical engineers working in this area. New people have been trained. Many of the new ones have extensive interdisciplinary training, such as postdocs in life sciences labs. The senior chemical engineers have, in some sense, retreaded themselves, and they now have life sciences expertise that allows them to bring their experience to bear on these problems. These interdisciplinary engineers are meeting their life sciences colleagues at the interface."
Another field of biomolecular engineering where chemical engineers are playing a major role is the area of molecular biocatalysis. According to chemistry professor George M. Whitesides of Harvard University, recent research in molecular biocatalysis has concentrated on three areas. "One of them is chiral synthesis," says Whitesides. "The emphasis on making enantiopure compounds has really made an impact on the pharmaceutical industry. . . . Ten years ago it was difficult to find a pharmaceutical company that had an active group in biocatalysis. I think it's now impossible to find a pharmaceutical company that doesn't." The second major focus of molecular biocatalysis, says Whitesides, is "the renaissance of glycobiology. The synthesis of sugars has always been an extremely difficult job, an extremely challenging job, for organic chemists. I think most organic chemists— even the hardcore synthesizers— would agree that enzymes have the
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SCIENCE/TECHNOLOGY wherewithal . . . to play a crucial enabling role." The third area, and the one that probably has the greatest potential for industrial impact, says Whitesides, "is environmentally friendly manufacturing. This ranges all the way from the reduction of waste streams by taking advantage of selectivity, to the elimination or reduction in use of organic solvents by working in aqueous solution, to the more mundane issues of using biocatalysis, typically in microbial form, for bioremediation. I think it's probably hard to find a topic in the U.S. now that is more prominent as a technical topic at the level of boards of directors than the environmental aspects of the manufacturing process." In all of these areas, he says, "there is a clear acceptance of the potential of biocatalysis. And now the challenge for the field is to find the proper niches and to find the proper justifications. And this will of course require coupling biological synthesis and biological analysis with the kind of scaleup,
process work, and economic analysis that engineers do best. So in some ways this is an ideal subfield for coupling the biological and the engineering disciplines." One researcher who is successfully coupling biology and engineering in this area is University of Pittsburgh chemical engineering professor Alan J. Russell. "Our research group is seeking to enhance enzyme stability and activity in the presence of organic solvents, at high temperatures (greater than 90 °C), and at high pressures (greater than 100 atm)," says Russell. For example, by adjusting the pressure of supercritical organic solvents, Russell and coworkers are able to manipulate the activity of lipase in the transesterification of methylmethacrylate with 2-ethylhexanol. "The dielectric constant of supercritical fluoroform can be tuned from approximately one to eight merely by increasing pressure from 850 to 4000 psi," says Russell, and dielectric-constant differences of this magnitude can cause
marked changes in enzyme properties. "The possibility now exists to alter predictably both the selectivity and activity of a biocatalyst merely by changing pressure," he says. Other researchers are focusing on finding new enzymes in organisms from unique environments. For example, chemistry professor Eric J. Toone and graduate student Michael Shelton at Duke University, in conjunction with biochemistry professor Michael W. W. Adams and coworkers at the University of Georgia, have been studying aldolase enzymes from hyperthermophilic microorganisms. "Hyperthermophilic" is variously defined as the ability of organisms to thrive at temperatures above 90 or 100 °C. Many hyperthermophilic microorganisms have been found near deep-sea hydrothermal vents that reach temperatures as high as 150 °C. In addition to the high temperatures, these environments are unique in having high levels of minerals, as well as gases such as methane, hydro-
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34
JANUARY 11, 1993 C&EN
gen sulfide, and hydrogen. Hence, the metabolic and biosynthetic pathways of hyperthermophilic microorganisms tend to be catalyzed by enzymes with unusual activities and substrate specificities. Toone, Shelton, Adams, and coworkers are examining a group of aldolases that catalyze reactions in which pyruvate reacts with aldehydes such as glyceraldehyde-3-phosphate to create 2-keto-4-hydroxybutyrate derivatives. In the reactions, pyruvate acts as a nucleophile and the aldehydes serve as electrophiles. Derivatives of 2-keto-4-hydroxybutyrate are synthetic precursors to a wide variety of structures found in biologically active compounds. Feasible transformations of 2-keto-4-hydroxybutyrates include decarboxylation to generate 2-deoxy aldose sugars, oxidative decarboxylation to give (3-hydroxy carboxylic acids, stereospecific reductive animation to provide a-amino-y-hydroxy carboxylic acids, and stereospecific reduction to yield a/y-dihydroxy carboxylic acids. Aldolases that are more flexible toward acceptance of different substrates could be even more useful than traditional aldolase enzymes from a synthetic standpoint. The researchers speculated that aldolases from hyperthermophilic microorganisms might need to be more flexible and efficient than conventional enzymes to operate at the high temperatures required. This speculation turned out to be correct. Aldolases from two hyperthermophiles they studied accept a broad range of nonnatural electrophiles at catalytic rates more than 100 times greater than those of previously known aldolases. The hyperthermophilic aldolases also accept several nonnatural nucleophiles in place of pyruvate, further enhancing their synthetic utility. New hyperthermophilic enzymes such as these could eventually prove to be commercially important. Owing to their ability to catalyze reactions in harsh environments, hyperthermophilic enzymes may see eventual use in the food industry (amylases and isomerases), the detergent industry (proteases), and the pulp and paper industry (xylanases and cellulases). In the long term, they could also find industrial applications in environmental control, petrochemicals production, and organic chemicals production from re-
newable resources. "Biochemical catalysis at last a-Aminoadipic acid flux plays key approaches the conditions role in antibiotic biosynthesis utilized by many industrial chemical conversions," Lysine says Adams. Lysine Another important teche-aminotransferase nique in the field of biomolecular catalysis is the engi1 -Piperideine-6-carboxylate neering of new enzymes. Dehydrogenase One important approach takes advantage of the diversity and specificity of I a-Aminoadipic acid I the immune system to cre16 ate catalytic antibodies. Cysteine -^J Valine A number of research — — ^ j ACV synthetase groups, including that of chemistry professor DonACV tripeptide ald Hilvert of Scripps Research Institute, develop Cyclase, Fe^ catalytic antibodies by synthesizing molecules that Isopenicillin N resemble the transition states of specific reactions. Epimerase They then use those transition-state mimics as immuPenicillin N nogens to induce the generation of antibodies with catalytic properties. Recent developments H from Hilvert7 s group have H9N included the design of anCH—(CH 2 ) 3 —CON tibodies that catalyze reHOOC CHoOCONHo actions not catalyzed by COOH natural enzymes, such as O-Carbamoyldeacetyl the Diels-Alder reaction, cephalosporin C and antibodies that work Dioxygenase methyltransferase in vivo to catalyze important metabolic reactions. H For example, the researchH9N I OChU ers recently showed that CH— (CH 2 ) 3 - CONan antibody with chorisN HOOC/ mate mutase activity can ^XH2OCONH2 o ^ ~ repair a defective biosynCephamycin C COOH thetic pathway in yeast. Although much work reInsertion of gene for lysine e-aminotransferase into bacteria creates recombinant strain mains to be done to optithat produces the antibiotic precursors O-carmize the chemical effibamoyldeacetyl cephalosporin C and cephaciency of catalytic antimycin C at levels 100% higher than in the wildbodies, this technology type strain can potentially provide Note: ACV = 5-0 -a-aminoadipyl)-L-cystehiyl-i>valine. Source: designer catalysts for a Li-Hong Malmberg, Wei-Shou Hu,, and • David — • • •H. •— Sherman of wide variety of engineerthe University of Minnesota ing applications. At the most biological In cell engineering, researchers try end of the biomolecular engineering spectrum, chemical engineers are get- to manipulate particular cell functing involved in the fine points of cell tions by changing some of the molecand tissue engineering—the manipu- ular properties of the cell or its surlation or reconstruction of cell and rounding environment. The key to tissue function using molecular ap- doing this is attaining an understanding of the regulatory and synthetic proaches. JANUARY 11, 1993 C&EN
35
SCIENCE/TECHNOLOGY
New pyruvate aldolases have enhanced synthetic utility OH SCH 3 NH OH OCH 3 NHCH(CH3)2 !
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Pyruvate aldolases that are more flexible toward acceptance of diverse substrates have been found in hyperthermophilic microorganisms. The increased flexibility enhances the utility of this class of enzymes for catalyzing formation of precursor compounds used to make a wide range of biologically active compounds Note: Shaded regions in products denote structural contributions from precursors. Source: Eric J. Toone and Michael Shelton of Duke University, and Michael W. W. Adams and coworkers at the University of Georgia
machinery that underlies such functions. Tissue engineering is the manipulation or reconstruction of tissue function by biochemical and cellular approaches. An example is a device in which 36
JANUARY 11, 1993 C&EN
"Everything we're talking about . . . in cell and tissue engineering is molecular/' says chemical engineering professor Douglas A. Lauffenburger of the University of Illinois, UrbanaChampaign. "Even if we're talking about mechanical stimuli, they're transduced through molecular mechanisms. And chemical engineers are really the kind of engineers who are trained to deal with these kinds of phenomena." For example, the standard way biologists look at cell receptors is in terms of their type or specificity, explains cell biologist H. Steven Wiley of the University of Utah Medical Center, Salt Lake City. "The quantitative aspect of these receptor systems [was] completely unappreciated. Only when we started working with chemical engineers and started actually using quantitative approaches to these problems did we start to see far more information than we ever saw by looking at what receptors or substrates were triggered." Wiley adds: "I would submit to you that the collaboration of chemical engineers and biologists not only provides you with an enhanced way of doing your experiments, but it actually can yield unique insights into a system that absolutely cannot be obtained in any other way. We will find things out about these systems that will never be found out by the work of either the engineers by themselves or the biologists by themselves. The whole is far greater than the sum of its parts." •
dopamine-releasing cells are encapsulated within a selectively permeable membrane that protects them from a host organism's immune system. Such a device was recently implanted in animal models of Parkinson's disease.
Process makes (/-olefins from carboxylic acids A group of chemical researchers has developed a new process that makes it possible to synthesize an important class of petrochemicals from renewable resources. The technique efficiently converts carboxylic acids to 1-alkenes (a-olefins) having one less carbon atom. It is of potential importance industrially because billions of pounds of a-olefins are produced annually for making detergents, lubricants, plasticizers, and polyethylene, among other applications (C&EN, Oct. 8,1990, page 20). Details of the work by chemists Joseph A. Miller, Jeffrey A. Nelson,
