Biochemical engineering

Summary

Biochemical engineers are responsible for designing and constructing those manufacturing processes that involve biological organisms or products made by them. Biochemical engineers take commercially valuable biological or biochemical commodities and design the means to produce those commodities effectively, cheaply, safely, and in mass quantities. They do this by optimizing the growth of organisms that produce valuable molecules or perform useful biochemical processes, establishing the most effective way to purify the desired molecules, and designing the operation systems that execute these processes, while adhering to a high standard of quality, purity, worker safety, and environmental cleanliness.

Definition and Basic Principles

Biochemical engineering involves designing and building those industrial processes that use catalysts, feedstocks, or absorbents of biological origin. Industrial processes used in food, waste-management, pharmaceutical, and agricultural plants are often called unit operations. Those unit operations used in combination with biological organisms or molecules include heat and mass transfer, bioreactor design and operation, filtration, cell isolation, and sterilization.

One of the main tasks of bioengineers is to optimize the production of commercially valuable molecules by genetically engineered microorganisms. Biochemical engineers design culture containers known as bioreactors that accommodate growing cultures and maintain an environment that keeps growth at optimal levels. They also create the protocols that separate the cultured cells and their growth medium from the molecule of interest and purify this molecule from all contaminating components. Biochemical engineers do not make the genetically engineered organisms that produce or do valuable things, but instead they maximize the capacities of such organisms in the safest and most cost-effective ways.

Biochemical engineers also design systems that degrade organic or industrial waste. In these cases, bioreactors house biological organisms that receive and decompose waste. They select the right organism or mix of organisms for the job at hand, establish environments that allow these organisms to thrive, and design systems that feed waste to the organisms and remove the degradation products.

A branch of biochemical engineering called tissue engineering combines cultured cells with synthetic materials and external forces to mold those cells into organs that can serve as a replacement for diseased or damaged organs. Biochemical engineers determine the forces, materials, or biochemical cues that drive cells to form fully functional organs and then design the bioreactor and associated instrumentation to provide the proper environment and cues.

Background and History

Biochemical engineering is a subspecialty of chemical engineering. Chemical engineering began in 1901 when George E. Davis, its British pioneer, mathematically described all the physical operations commonly used in chemical plants (distillation, evaporation, filtration, gas absorption, and heat transfer) in his landmark book, A Handbook of Chemical Engineering.

Biochemical engineering emerged in the 1940s as advancements in biochemistry, the genetics of microorganisms, and engineering shepherded in the era of antibiotics. World War II created shortages in commonly used industrial agents; therefore, manufacturers turned to microorganisms or enzymes to synthesize many of the chemicals needed for the war effort. Growing large batches of microorganisms presented scaling, mixing, and oxygenation problems that had never been encountered before, and biochemical engineers solved these problems.

During the 1960s, advances in biochemistry, genetics, and engineering drove the creation of biomedical engineering, which is the application of all engineering disciplines to medicine, and separated it from biochemical engineering. During this decade, biochemical engineers developed new types of bioreactors and new instrumentation and control circuits for them. They also made breakthroughs in kinetics (the science that mathematically describes the rates of reactions) within bioreactors and whole-cell biotransformations.

The 1970s saw the development of enzyme technologies, biomass engineering, single-cell protein production, and advances in bioreactor design and operation. From 1980 to 2000 there was a virtual explosion in biochemical-engineering advances that had never been seen before. The advent of recombinant DNA and hybridoma technologies, cell culture, molecular models, large-scale protein chromatography, protein and DNA sequencing, metabolic engineering, and bioremediation technologies changed biochemical engineering in a drastic and profound way. These technologies also presented new challenges and problems, many of which are still the subject of intense research and development.

How It Works

Bioreactors. Bioreactors that utilize living cells are typically called fermenters. There are several different types of bioreactors: mechanically stirred or agitated tanks; bubble columns (cylindrical tanks that are not stirred but through which gas is bubbled); loop reactors, which have forced circulation; packed-bed reactors; membrane reactors; microreactors; and a variety of different types of reactors that are not easily classified (such as gas-liquid reactors and rotating-disk reactors). Biochemical engineers must choose the best bioreactor type for the desired purpose and outfit it with the right instrumentation and other features.

Bioreactor operation is either batch-wise or continuous. Batch-wise operation or batch cultures include all the nutrients required for the growth of cells prior to cultivation of the organisms. After inoculation, cell growth commences and ceases once the organisms have exhausted all the available nutrients in the culture medium. A modification of this type of operation is a fed-batch or semi-batch operation in which the reactants are continuously fed into the bioreactor, and the reaction is allowed to go to completion, after which the products are recovered. Continuously operated bioreactors, use “continuous culture systems” that continuously feed culture medium into the bioreactor and simultaneously remove excess medium at the same rate. Batch-culture bioreactors work best for fast-growing biological organisms. Slow-growing organisms usually require continuous-culture bioreactors.

Several factors influence the success of bioreactor-based operations. First, choosing the right strain to make the desired product is essential. Second, the culture medium and growth conditions must optimize the growth of the chosen organism. Third, supplying the culture with adequate oxygen requires the use of agitators or stirring equipment that must operate at high enough levels to aerate the culture without severely damaging the growing cells. Fourth, the bioreactor must have sensors to measure accurately the physical properties of the culture system, such as temperature, acidity (pH), and ionic strength. Fifth, the bioreactor should also be equipped with the means to adjust these physical properties as needed. Finally, the bioreactor must be integrated into a network of peripheral equipment that allows automated monitoring and adjustment of the culture's physical factors.

Separation. Once a bioreactor makes a product, separating this molecule or group of molecules from the remaining contaminants, byproducts, and other components is an integral part of preparing that molecule for market.

There are several different separation techniques. Filtration separates undissolved solids from liquids by passing the solid-liquid mixture through solids perforated by pores of a particular size (like a membrane). If the liquid is viscous or the particle size of the solid is too small for filtration, centrifugation can separate such solids from liquids. The liquid samples are loaded into centrifuges, which spin rotors at very high speeds. This process creates pellets from the solids and separates them from liquids. Neither filtration nor centrifugation can separate dissolved components from liquids.

Adsorption and chromatography can effectively separate dissolved molecules. Adsorption involves the accumulation of dissolved molecules on the surface of a solid in contact with the liquid. The solid in most cases consists of a resin made of porous charcoal, silica, polysaccharides (complex chains of sugars), or other molecules. Chromatography runs the liquid through a stationary medium packed into a cylindrical column that has particular chemical properties. The interaction between the desired molecules and the stationary medium facilitates their isolation. Other types of separation techniques include crystallization, in which the molecule of interest is driven to form crystals. This effectively removes it from solution and facilitates “salting out,” in which gradually increased salt concentrations precipitate the molecules of interest, or contaminating molecules, from a liquid solution.

Sterilization. If a culture of genetically engineered organisms is used to produce a commercially useful product, contamination of that culture can decrease the amount of product or cause the production of harmful byproducts. Therefore, all tubes, valves, the bioreactor container, and the air supplied to it during operation must be effectively sterilized before the start of any production run.

Heat, radiation, chemicals, or filtration can sterilize equipment and liquids. One of the most economical means of sterilization is moist steam. Calculating the time it takes to sterilize something depends on the initial number of organisms present, the resilience of those organisms to killing with the chosen agent, the ability of the air or liquid to conduct the sterilizing agent, and length of time the organisms are exposed to the sterilizing agent.

Applications and Products

Pharmaceuticals. Hundreds of pharmaceuticals are proteins made by genetically engineered organisms. Because these reagents are intended for clinical use, they must be produced under completely sterile conditions and are usually grown in disposable (plastic), prepackaged, sterile bioreactor systems. A variety of wave bioreactors, hollow-fiber membrane bioreactors, and variations on these devices help grow the cells that make these products.

Some of the proteins made by genetically engineered cells are enzymes. Genentech, for example, makes dornase alfa, an enzyme that degrades DNA. This enzyme is made by genetically engineered Chinese hamster ovary (CHO) cells and is purified by filtration and column chromatography. Dornase alfa is administered as an inhalable aerosol to allay the symptoms of cystic fibrosis. Other therapeutic enzymes include clotting factors such as Helixate FS (native clotting factor VIII made by CSL Behring), NovoSeven (clotting factor VII made by Novo Nordisk) to treat hemophilia, and Fabrazyme or Replagal (agalsidase alfa) to treat Anderson-Fabry disease.

Other pharmaceuticals are peptide hormones. Serostim and Saizen are commercially available versions of recombinant human growth hormone. Both products are made with cultured mouse C127 cells in bioreactors. Human growth hormone is used to treat children with hypopituitary dwarfism or those who experience the chronic wasting associated with AIDS.

Therapeutic proteins are normally made in the human body under certain conditions, and synthetic versions of these proteins that are made in labs can be used as medicine. For example, human cells make a protein called interferon in response to viral infections, but synthetic interferon can also be used to treat multiple sclerosis. Two synthetic forms of interferon-1β, Rebif, which is made in CHO cells by EMD Serono, and Avonex, also made in CHO cells by Biogen Idec, serve as treatments for multiple sclerosis. Alefacept (brand name Amevive), which is made by Astellas Pharma, is a fusion protein that blocks the growth of specific T cells (immune cells). No such protein exists in the human body, but alefacept is used to treat psoriasis and various cancers.

These are only a few examples of the hundreds of pharmaceutical compounds made by genetically engineered organisms in bioreactors designed by biochemical engineers.

Monoclonal Antibodies.Monoclonal antibodies are Y-shaped proteins secreted by specific cells of the immune system that precisely bind to specific sites (epitopes) on the surface of foreign invaders, and act as guided missiles that facilitate the destruction or neutralization of the foreign invaders.

Immune cells called B lymphocytes secrete antibodies, and the fusion of these antibody-producing cells with myelomas (B-cell tumor cells) produces a hybridoma, an immortal cell that grows indefinitely in culture and secretes large quantities of a particular antibody. Antibodies made by hybridoma cells can bind to one and only one site on a specific target and are known as monoclonal antibodies.

Monoclonal antibodies are powerful clinical and industrial tools, and by growing hybridoma cell lines in bioreactors, biotechnology companies can produce large quantities of them for a variety of applications.

Mouse monoclonal antibodies end with the suffix “-omab.” Tositumomab (brand name Bexxar) was approved by the Food and Drug Administration (FDA) for treatment of non-Hodgkin lymphoma in 2003.

Chimeric antibodies are humanized monoclonal antibodies, and have the suffixes “-ximab” (chimeric antibodies that are about 65 percent human) or “-zumab” (humanized antibodies that are about 95 percent human). Cetuximab (Erbitux) is a chimeric antibody that was approved by the FDA in 2004 for the treatment of colorectal, head, and neck cancers. Bevacizumab (Avastin) is a humanized antibody approved by the FDA in 2004 that shrinks tumors by preventing the growth of new blood vessels into them.

Human monoclonal antibodies are made either by hybridomas from transgenic mice that have had their mouse antibody genes replaced with human antibody genes, or by a process called phage display. Human monoclonal antibodies end with the suffix “-mumab.” The first human monoclonal antibody developed through phage display technologies was adalimumab (Humira), which was approved by the FDA to treat several immune system diseases.

Tissue Engineering. Making artificial organs for transplantation represents a unique challenge. Bioreactors tend to grow cells in two-dimensional cultures, but organs are three-dimensional structures. Thus, biochemical engineers have designed synthetic scaffolds that support the growth of cultured cells and mold them into structures that bear the shape and properties of organs. They have also designed special bioreactors that subject cells to the physical conditions that induce the cells to form the tissues that compose particular organs.

People often need cartilage repair or replacement, but bone and cartilage form only when their progenitor cells are subjected to mechanical stresses and shear forces. Biochemical engineers have grown bone by seeding bone marrow stem cells on a ceramic disc imbued with zirconium oxide and loading these discs into bioreactors with a rotating bed. Cartilage biopsies are taken from the nose or knee and grown in a bioreactor in which the cells are perfused into a complex sugar called glycosaminoglycan (GAG). This engineered cartilage is then used for transplantations. Such experiments have established that nasal cartilage responds to physical forces similarly to knee cartilage and might substitute for knee cartilage.

Heart muscle is grown in bioreactors that pulse the liquid growth medium through the chamber under high-oxygen tension. Blood vessels are grown in two-chambered bioreactors and contain a reservoir of smooth muscle cells and a chamber through which culture medium is repeatedly pulsed.

Food Engineering. Companies making foods that require fermentation by microorganisms or digestion of complex molecules by enzymes use bioreactors to optimize the conditions under which these reactions occur. Biochemical engineers design the industrial processes that manufacture, package, and sterilize foods in the most cost-effective manner.

Starch is a polymer of sugar made by plants and is a very cheap source of sugar. To convert starch into glucose, enzymes called amylases are employed. These enzymes are often isolated from bacteria or fungi, and some are even stable at high temperatures. Degrading starch at high temperatures often clarifies it and rids it of contaminating proteins.

Lactic acid fermentation metabolizes simple sugars to lactic acid and is commonly used in the production of yogurt, cheeses, breads, and some soy products. Cheese production begins with curdling milk by adding acids such as vinegar that separate solid curds from liquid whey and an enzyme mixture called rennet that comes from mammalian stomachs and coagulates the milk. Starter bacterial cultures then ferment the milk sugars into lactic acid. Yogurt is made from heat-treated milk to which starter cultures are added. The acidity of the culture is monitored, and when it reaches a particular point, the yogurt is heated to sterilize the culture for packaging.

Ethanol fermentation converts simple sugars to ethyl alcohol and is used in the production of alcoholic beverages. The most common organism utilized for ethanol fermentation is the baker's yeast, Saccharomyces cerevisiae. Malted barley is the sugar source in beer production, and grapes are used to make wine. Beer production involves the extraction of wort, a sugar-rich liquid from barley, which is treated with hops to add aroma and flavor and is then fermented by yeast to form beer. For wine production, the juice from crushed grapes is fermented by yeast for from five to twelve days to generate ethanol. For most red wines and some white wines, the mixture is fermented a second time by malolactic bacteria that degrade the malic acid in the wine, which has a rather harsh, bitter taste, to lactic acid. This lowers the acidity of the wine.

Biofuel Production. Burning of fossil fuels as an energy source is not sustainable, since the supply of these fuels is finite and their combustion generates greenhouse gases such as carbon dioxide (CO₂), sulfur dioxide (SO₂), and nitrogen oxides. First-generation biofuels (biodiesel and bioethanol) utilize biomass from cultivated crops such as corn, sugar beets, and sugar cane. This results in the unfortunate consequences of tying up large swathes of farmland for fuel production and raising food prices. Second-generation biofuels come from grasses, rice straw, and bio-ethers, which are economically superior to first-generation biofuels. Third-generation biofuels show the most ecological and economic promise and come from microalgae. The oil content of some microalgae can exceed 80 percent of their dry weight, and since they use sunlight as their energy source and atmospheric CO₂ as their carbon source, microalgae can produce substantial amounts of oil with little material investment.

Microalgae can be grown in open ponds, which ties up land, or special bioreactors called photobioreactors. The fast-growing microalgae are harvested and then liquefied by microwave high-pressure reactors. Oils extracted from the algal species Dunaliella tertiolecta at 340 degrees Celsius for sixty minutes had physical properties comparable to fossil fuel oil.

Waste Management. The removal of pollutants from air and water provides a large global challenge to environmental engineers. While there are nonbiological ways to degrade pollution, biological strategies represent some of the most innovative and potentially effective ways to remediate pollution.

To treat polluted air, it is piped through a biofilter, which consists of an inert substance called a carrier. Nutrients are trickled over the carrier, and consequently the carrier is colonized by biological organisms that can degrade the pollutant. Devices called bioscrubbers eliminate pollutants such as hydrogen sulfide (H₂S), which smells like rotten eggs, or SO₂, by dissolving the air pollutants in water and running the water into a bioreactor where the pollutants are degraded. For air pollutants that are poorly soluble in water, such as methane (CH₄) or nitric oxide (NO), hollow-fiber membrane bioreactor (HFMB) systems that house a robust population of biological organisms that can degrade gas-phase pollutants effectively treat air polluted with such molecules. Many of these same strategies can also treat polluted water.

Bioreactor landfills were designed to accelerate the degradation of municipal solid waste (MSW) in landfills. Bioreactor landfills use microorganisms to degrade solid wastes, but they also drain the water (leachate) that moves through the landfill, clean it, and recycle it back through the landfill in a process called leachate recirculation. The design of a bioreactor landfill requires extensive knowledge of the surroundings, the nature of the MSWs to be treated, and the quality of the water that becomes the leachate.

Careers and Course Work

Foundational course work for biochemical engineering includes classes in biology, chemistry, physics, advanced mathematics, and computer programming. Additional course work in basic engineering concepts, like statics, dynamics, electronics, and thermodynamics are also necessary to train as a biochemical engineer. These would be followed by advanced courses in chemistry and chemical engineering. To work as a biochemical engineer, a bachelor's degree in biological, biochemical, or chemical engineering is required, as is becoming registered as professional engineer (PEng). Advanced degrees (MS or PhD) are required for those who wish to work in academics or professional engineering research. In industry, advanced degrees are typically not required for entry-level jobs but are helpful for promotions to managerial or supervisory positions.

Biochemical engineering is a highly collaborative field, and an engineer must be able to work well with other professionals. Therefore, good communication skills are essential. Biochemical engineering is a highly analytical field that requires skill and an affinity for mathematics and chemistry as well as problem solving. Since much of the problem solving occurs on a computer, the ability to visualize and design processes on computers has become an integral part of the field.

If a company employs biological organisms or enzymes for biological or chemical conversions, that company requires the expertise of a biochemical engineer. The majority of biochemical engineers work in chemical process industries (CPI), which include the chemical, gas and oil, food and beverage, textile, and agricultural sectors. Other enterprises that employ biochemical engineers include biotechnology and pharmaceutical companies, petroleum refining and oil sands extraction, waste management, paper and pulp manufacturing, farm machinery, construction and engineering design companies, and environmental companies and agencies. Government-employed biochemical engineers may work for the Departments of Energy or Agriculture, the EPA, or other such agencies.

The development of new technologies in fields like genetic engineering, biomedicine, bioinstrumentation, biomechanics, waste management, and alternative energy development are driving new employment opportunities for biochemical engineers. According to the Bureau of Labor Statistics' Occupational Outlook Handbook, bioengineers and biomedical engineers earned median wages of $92,620 in 2020. The handbook projects an annual job growth rate of 6 percent from 2020 to 2030.

Social Context and Future Prospects

Two aspects of biochemical engineering can be cause for concern to the general public. First, biochemical engineers work with genetically engineered organisms. Many people have never completely made peace with the use of such organisms, despite the fact that many of the items people consume on a regular basis, from seasonal flu vaccines and other medicines to the foods they eat, are made by genetically engineered organisms. Nevertheless, fear of genetically engineered organisms remains. For example, despite repeated tests establishing that genetically engineered foods are as safe as food from nongenetically modified crops, some people still feel the need to label genetically engineered food as Frankenfood. As long as this fear persists, the work of biochemical engineers will make some people uncomfortable. Second, biochemical engineers tend to work for large industries that are sometimes painted as inveterate polluters by environmental groups or as greedy, unconcerned capitalists by consumer-advocate groups; however, many of these companies also abide by strict environmental standards and engage in humanitarian work.

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