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Bioengineering
General Discussion Bioengineering Charles Cooney: I’d like to share some observations relevant to the challenges we face in moving the frontier of biochemical engineering forward. Specifically, there are four points in the context of what we’re not doing now as well as we could and what is important to do in the future to support both research and education. First, the biochemical process industry is large and parallels the chemical process industry that we’re all familiar with. Today, the excitement in biochemical processing is associated with recombinant DNA products. There was over $ 1 billion in sales from five recombinant DNA-derived products in 1989, and the market is growing. This industry is driven by the new scientific discoveries, which Jay Bailey pointed out very well. Applications of this new science demand new technology to translate the science of recombinant DNA, protein engineering, etc. into commercial practice. There is not only opportunity and challenge but also responsibility for chemical engineering. What should we do to meet this challenge? How do we train students in a dynamic, technological environment to understand and respond to this new science and translate it into technology? These questions have been addressed in a number of different areas, but an important point has been missed. We need to train students to solve problems, not just to understand solutions and fundamentals. Solving problems and knowing how to make use of fundamentals is a mission that we must address. The second observation is that we have an interesting competition between genetic engineering and chemical process engineering in solving biochemical process problems. This competition has several implications. One is to identify a process problem, then have the biologist create molecular 485
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solutions via genetics to solve it. Alternatively, we can seek solutions via traditional or innovative chemical processing. It’s imperative that we train our students to appreciate the biology, on the one hand, and to understand the chemistry, on the other. Most important, we need to train our students and the people in our laboratories to understand and contribute to a multidisciplinary effort. This is one of our biggest challenges, one that I don’t think we’ve addressed adequately thus far. My third observation is that, when looking at the range of processes for handling proteins that have evolved recently, two technologies dominatefiltration and adsorption-though occasionally other methods are used. These are the domain of the chemical engineer. In two decades, we’ve done a reasonable job of understanding the fluid dynamics of processes such as ultrafiltration and microfiltration. Yet, the chemistry of filtration processes is poorly understood, i.e., the interaction between proteins and the surface of the filter and between the protein molecules and other particles that bind to the surface. Consequently, there are no predictive models for filtration processes, despite the significant amount of modeling that’s been done. Second, adsorption processes such as chromatography are critical to this industry. Again, our understanding of protein interactions with the surface and with each other is weak. Our understanding of the alternatives to these technologies, such as extractive processes, is also poor. We need to better understand both the alternatives and the fundamental chemistry of the process. Lastly, process synthesis is important in this field. The biologists dominate process synthesis in the recombinant DNA and protein manufacturing business. What limitations prevent chemical engineers from making contributions? There are two: an almost complete absence of predictive models based on fundamentals and a poor understanding of the physical and chemical properties of biological materials. These issues need to be addressed in both teaching and research. Gregory Stephanopoulos: Jay Bailey underlined the enormous opportunities for chemical engineers in biochemical engineering. We must answer the question, what can chemical engineers do here better than biologists? One example is introduction of rate processes in describing biological systems, since biologists probably are not going to do it. They are also not interested in applied biology, represented, for example, by solving the problem of hemoglobin synthesis that Jay mentioned. Does a chemical engineer require specialized training to work in molecular biology? Yes, but we do have examples of chemical engineers trained to do gene splicing. Jay mentioned one, and we have others at MIT. The important point is that these students on their own initiative learned gene splicing by talking the professors into letting them take these laboratory courses. About a
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year later, these students were producing results by putting a gene to do something useful into a microorganism or taking out a gene that the organism does not need and that we don’t want. This technology has been around for 10 years, but biologists have not applied it to the kind of problems that we are interested in. We need courses in this area. The limitation is not the eagerness of our students nor their capacity to absorb the material. But can we supply them with the tools and the courses that they need to assimilate these new concepts and techniques? It won’t be easy, because there are not many chemical engineering faculty trained in this area, and these courses are very expensive. My final point concerns the single most important development that brought about the explosion in biological sciences-the development of techniques to separate and accurately characterize proteins and other molecules that exist in the cell. This key capability enabled the discovery of restriction enzymes and other phenomena. These separation methods have been mainly physical and physicochemical techniques, not involving organic chemistry. Biologists failed as long as they tried to accomplish these tasks with organic chemistry. Gel chromatography and blotting techniques led to these results. We have an opportunity to improve these techniques, and they are the prototypes of processes by which proteins or other macromolecules eventually will be separated on a large scale.
Edwin Lightfoot: I have a few remarks on topics that may have been missed. First, we can divide biotechnology into the areas of bioprocessing, which is truly a chemical engineering activity, and metabolic engineering, where we’re concerned with the details of the living organism. Both of these have big opportunities for us. I’ll begin with an issue related to Art Humphrey’s plant cell culture example. In the early days of penicillin production, it was found that you could take molds that normally grow on the surface of water, or on wet surfaces, and submerge them into a deep tank where they would still grow. The big problem was to supply oxygen to them, because oxygen has a low solubility in water. Small submerged fermentation cultures have dominated world wide biotechnology ever since, but they aren’t suitable for a lot of purposes. A classic example is mold spores, which are not normally formed in submerged fermentation cultures. This suggests going a different route. One can find some good leads in looking at the diffusion capacity of water and air. Air will transport oxygen 500,000 times better than water. Thus, molds and other plants grew in air originally for a good reason. Consequently, there’s increasing interest in solid substrate fermentations, of which the prototype is the malting industry, where air is blown through a damp, not wet, solid, granular mass. This method has several advantages. It is the basis
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for a great many foodstuffs, such as soy sauce. It can also be used for processes on the horizon, like biopulping of wood, where wood chips are inoculated with molds, and so forth. Radical changes in fermentation technology can solve some basic problems and produce substantially increased effectiveness. The essence of living systems is the complex reaction networks that produce life processes, and those are a natural place for chemical engineers to get involved. We can’t beat the biochemists on their own ground, because they’re trained to handle these multitudinous biochemical reactions and to learn something about their interrelationships at a qualitative level. Until recently, few of them addressed systems aspects. There are three that I think are particularly important. One is getting material balances when you have thousands of species present. It’s sometimes important to find out how many reactions are being used and at what rates. Charlie Cooney has pioneered that area. The most recent work I’m aware of is from EastmanKodak; John Hamer and Jim Liao have used singular value decomposition techniques to get relations between metabolites. By doing that they can find out when the fermentations are off course, and perhaps even when they become contaminated, quite early. The second is sensitivity analysis, or how to decide what enzyme out of hundreds you want to increase the activity of. The biochemists call that control analysis. It’s an important area that I think Jay Bailey touched on. The final one is dynamics, and it is important to realize how many diseases are essentially dynamic and have much in common with poorly controlled manufacturing processes. Diabetes is one of the most interesting to me at the moment. The whole purpose of insulin management is to minimize the time-average sugar levels in the blood without going below a lower level too often, resulting in insulin shock. That’s similar to problems in a manufacturing process, because you don’t have access to all of the information you need. All you can do is measure sugar levels at intervals that are too far apart to be really controlled. That gets pretty close to the heart of modern chemical engineering. Clark Colton: I have comments in three areas. The first comment concerns the motivation for research in biomedical areas. I believe the primary factor is that this field is rich in intellectually challenging issues that provide good problems for training chemical engineers. As Channing Robertson pointed out, living organisms are complex bioreactors. In animals, one finds that life processes are determined largely by transport phenomena, thermodynamics, and reaction kinetics, as well as an extraordinary diversity of molecular and supramolecular interactions. In his review of the intellectual origins of chemical engineering to be presented at the Convocation, Skip Scriven focused largely on our growth out of industrial chemistry. Although the lineage is far less direct, one could make a case that the intellectual
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forebears of modern chemical engineering include some of the physicianphysiologists of the 19th century. These scientists set out to show that the functions of organisms could be explained on the basis of the physicochemical laws of nature. One example is Jean L. M. Poiseuille, who was interested in the circulation of blood through the cardiovascular system. His objective, to test the then-popular hypothesis that blood flow derived from the motive force of red cells, led him to experiments on pressure-flow relationships with pure fluids in fine glass capillary tubing, resulting in the classic law that bears his name, published in 1840. Poiseuille’s experiments were conducted with great care; his measurements of the temperature dependence of what is now called viscosity agree to within 0.5% of modern values for water. Perhaps the quintessential example of these researchers is Adolph E. Fick, who began his studies in physics and mathematics, switched to medicine, and eventually became a professor of anatomy and physiology. In the course of his career during the second half of the 19th century, Fick’s diverse contributions included molecular diffusion in liquids and porous membranes, solid mechanics applied to bone joints and muscles, hydrodynamics in rigid and elastic tubes, thermodynamics and conservation of energy in the body, optics of vision, sound, and bioelectric phenomena. We know him for the differential equations he developed ( 1855-1 857), known as Fick’s laws of diffusion, that are taught to all undergraduate chemical engineers. He is at least as renowned in the medical profession for another law, Fick’s law of the heart. In 1870, he developed a method for calculating cardiac output from measurements of oxygen consumption and of oxygen concentration in the venous and arterial blood. His principle is nothing more than a material balance for oxygen around the pulmonary circulation! My last example is Adrian V. Hill, who received the Nobel Prize for Physiology and Medicine in 1922 for his work on the production of heat and lactic acid by muscle. In 1928, he published an extensive paper on mathematical aspects of reaction-diffusion problems associated with diffusion of oxygen and lactic acid through tissue. His paper presaged the classic works of Thiele, Damkohler, and Zeldovich a decade later. I could cite other examples, notably Hermann von Helmholtz, but I think my point is clear. A secondary motivation for research in biomedical areas is the significant growth in hiring of chemical engineers by the health care industry in the past decade. For example, artificial kidneys are now used to treat more than 300,000 patients worldwide, and commercial sales of associated products are more than $1.5 billion per year. In the next decade, we are likely to see other new therapies open up similar markets, possibly with implanted devices. Development of these new technologies will require a much better understanding of the interaction of materials with biological macromolecules, cells, and tissues, some of which Channing referred to.
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My second comment concerns labels in bioengineering. There was a time when those in biochemical engineering were concerned exclusively with production of materials by fermentations of microorganisms and those in biomedical engineering with physiological processes and medical devices. With the advent of recombinant DNA technology, especially its application to animal cells, and the growth of “biotechnology,” a term which has been applied to a multiplicity of disparate areas, the distinctions have blurred. For example, some areas of research, such as animal cell bioreactors, interactions between synthetic and biological materials, and separation processes for proteins and cells, fall within both provinces. Likewise, the common knowledge base required in these areas of bioengineering has broadened to the point of substantial overlap, encompassing such fields as biochemistry, biophysics, cell biology, and immunology. My third comment echoes the point made by Jay Bailey, that our undergraduates should be exposed to biology. My position is not based on its utility for later research or its role in professional training. Rather, I believe the time has come that individuals cannot consider themselves scientifically literate without some understanding of developments in biology. The revolution in the biological sciences that began in the 1960s has proceeded at a rapid pace, and the rate of development of new knowledge and understanding shows no signs of abating. We pride ourselves on being the most broadly trained of engineers, with backgrounds in mathematics, physics, and chemistry. I suggest that biology be added to that list, as it should be for any educated scientist. Sheldon Zsukoff: There’s an issue in the production of pharmaceuticals that hasn’t been brought up by the speakers, yet it’s pertinent to the changing character of chemical engineering, and that is regulation. Anytime you introduce a new material that gets into the human body, you need the approval of the Food and Drug Administration. If you do experiments on a small scale and get your approvals from the agency, those approvals are not only for the material that you’ve produced but also for the process by which you produced them. If you change your process when you go commercial or produce larger lots of the material, you have to go through the approval process again. Timeliness in getting the product out to the marketplace is crucial in this business, as in many others. It’s important for chemical engineers to be involved early so that when FDA approval is obtained, you know that you have a process that is scalable to commercial size and will turn out a product having the same properties and efficacy as the material produced at small scale. Daniel Wang: Bioengineering is really about practicing the fundamentals of chemical engineering. We do things well quantitatively, whereas biolo-
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gists don’t. Take Sheldon Isakoff’s point about the FDA and clinical trials. Do you realize that it costs more to put a product through a clinical trial than to make it? It’s about $100 million to $150 million per product, and one out of three is successful. Any big company will have to spend at least $100 million to get out one product. Let’s look at pharmacokinetics and the work done with compartmental analysis. We should become involved with the biology of clinical trials in a quantitative way. Can we do more than just say the profile in compartments of the body follows a certain pattern? Engineers have to start looking into this other side of regulatory activities. We also totally lack a leadership role in the proper places, such as Washington. Why does the FDA ask us questions about the process? They don’t know what the three-dimensional structure is. The covalent structure is easier to define, the secondary and tertiary structures are more difficult. The only way they can be sure of what’s happening is to make certain our processes are identical, because all else is unknown. Why are the biologists doing everything? Because they have a presence there. We have to make our own destiny. One example is involvement with clinical trials. We need to do more, because we can do things in a quantitative way. Edward Merrill: I feel like Don Quixote against the windmills with respect to blood viscosity, the study of which, as Clark alluded, began with Poiseuille, a French physician in the 1700s. Would you believe that today, if you go through the index of Harrison’s Principles of Internal Medicine, you won’t find a single reference to the viscosity of anything, including blood, so the internist has no idea of the concept? For 25 years, I’ve been talking to physicians about the importance of viscosity, and they look at me with glazed eyes. We sometimes have to work hard on our colleagues in other disciplines to bring their attention to what we would have thought was an important concept. My second comment is apropos of Channing Robertson’s remarks, which I admired. In regard to polymers, it seems to me that the time has come to adopt again a unifying approach like that of Charles Tanford, professor of biochemistry at Duke University, who wrote the book Physical Chemistry of Macromolecules comparing biopolymers with synthetic polymers. In polymer synthesis, let’s look at the synthesis of peptides, amino acid by amino acid, and the desynthesis of peptides by sequencing, and bring this into our curriculum. William Deen: I’d like to emphasize a point that came up in Clark’s remarks and Channing’s remarks. That is, the exchange of information between chemical engineering and medicine or the life sciences is in both directions. Several examples were cited of how we can affect medical practice
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through development of devices or novel therapies. We can also affect medical education by contributing to its scientific base. Further, we can learn from developments in the medical sciences. Clark pointed out two very nice historical examples, Poiseuille’s law and Fick’s law. Another more recent example is the concept of carrier-facilitated transport, which originated to explain special properties of biological membranes and has since found application in chemical separations processes. At least until recently, membrane biophysicists have been way ahead of engineers in understanding the physics of transport through membranes. That understanding provides a basis for modern membrane separations, including ones becoming important in biotechnology. It’s important for us as a profession to maintain this window, this area of focus, even though the health care industry will probably never provide a large number of career opportunities for chemical engineers. As Clark mentioned, the health sciences provide interesting problems for research, and the exchange of information occasionally inspires new ideas on how to accomplish a chemical transformation or separation.
Thomas Edgar: What percentage of B.S. chemical engineers would you estimate go into the health care, pharmaceutical, or biorelated industries today, and what percentage do you forecast 10 years from now? Bill Deen made it sound like there are not that many opportunities. I am not talking about Ph.D.’s, just B.S. engineers. Clark Colton: In the past few years, there has been a marked increase in hiring of graduate chemical engineers by the pharmaceutical companies in the bioprocessing area and, to a smaller extent, by the health care companies. I believe there has also been an increase in hiring of B.S. chemical engineers, although I don’t think the demand will ever be gigantic at that level. Thomas Edgar: I’m just trying to get perspective. Larry Thompson showed us a curve of engineers hired by the microelectronics industry, and I’m trying to understand the relative magnitude of demand here. Edwin Lighrfoot: Tom, you’re being unfair because you’re not counting the Ph.D.’s, and that makes considerably less people. It takes a fair amount of specialization in an area like this. Thomas Edgar: I’m not being unfair, I’m just asking a question. L. E. Scriven: It’s quite evident in Minneapolis, which is the home base of General Mills, Pillsbury, International Multifoods, and so on, that the process food industry has absorbed thousands of chemical engineers. They may not be doing the kind of biotechnology that you’re speaking of, but their industry certainly is an important consumer of chemical engineers. The
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conversion from food technologists to chemical engineers has been made. There appears to be a similar trend in other agriculture-based process industries. Arthur Humphrey: If you lump all of the B.S. students who go into medicine, veterinary science, and dental science, and add all of those going into the health care, pharmaceutical, food, and agricultural-based industries, you get up to almost 25% of the chemical engineering profession. You have to define food and agriculture on a very broad base. My own concept is that this field is probably going to utilize 25 to 30% of the chemical engineers when it reaches an equilibrium. James Wei: The AIChE had a survey on that subject. I think that the food industry is hiring 1.7% so far. Daniel Luss: I want to raise an issue that concerns the training of chemical engineering graduates who conduct research in biochemical engineering. Every major department now has a research program in biochemical engineering, and they attract many of the most talented students who enter the graduate programs. The proper training of chemical engineering students carrying out research in this area requires that they take a large number of courses in the biological sciences. Thus, if they work in a traditional chemical engineering area, a large fraction of their training will not be utilized. Clark Colton: I disagree. It’s true that students doing graduate research in bioengineering may have to take some specialized subjects in the biological or medical sciences, but this is no more limiting than for any of the other relatively new areas we’ve been discussing. It’s important that students are exposed to sufficient graduate chemical engineering course work and that there be substantial chemical engineering content in their research. With this proviso, these students don’t lose the breadth of their undergraduate training for applications in industry. The limitations are greater if one goes into academia, because one’s thesis often fixes one’s research area, and it’s difficult to change fields, especially as an assistant professor. When I started out, there were few if any industrial jobs related to the research of my students. That situation has changed today. My earliest students either went into teaching or they went into industry. Those who went into industry did the same things that other chemical engineers did because they had appropriate training and were able to use it. Daniel Luss: Several faculty members working in this area insist that their students take a large number of courses in the biological sciences. I’m told that it’s essential for anyone who wants to do research in this field. I raise the question whether it’s the best training for a student who will not be
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employed in this area. It’s clear that the number of available teaching positions in chemical engineering departments for these graduates is declining, as most departments already have young faculty members for biochemical engineering. As a consequence, most of the graduates may have to find industrial employment, and at present the biochemical industry does not hire very many such graduates. Clark Colton: Whether there is a problem depends on the environment the student is in and the nature of departmental requirements. In our department, all doctoral students must pass a qualifying exam that is based on the core areas of fluid mechanics and transport, thermodynamics, and kinetics and reactor engineering. Although there are no formal course requirements for the Ph.D., in practice virtually all entering students enroll in the associated core graduate subjects. Students are also expected to take a reasonable number of additional graduate subjects in the department. There’s a formal requirement for a minor, and it’s in this context that most students doing bioengineering research take biology or medical science subjects outside the department. Students who receive this kind of exposure don’t lose their chemical engineering identity or capabilities. They can function well in industry. If anything, they enrich the profession.
Edwin Lightfoot: I have two students in this category. The first started in
separations, and he’s taken a lot of biology, but what he’s really working on is NMR techniques. He’s going back to the basic quantum mechanics to study NMR techniques. The other student is working on diabetes, and she’s taken advanced processing control courses because this is a control problem. Alan Hatton was one of these to a degree, as was Abraham Lenhoff, now at Delaware. These people have done very well in fields that are quite different from where they started. This is a bum rap. Robert Cohen: I believe this is more than semantics. The problem that Dan brings up is contained in the way he discusses it. If you think of graduate training, the word “train” is what I object to. Graduate education is different from job training, and if you’re picking a good problem, there’s educational value in that, and the specific field is more or less irrelevant. Gregory Srephanupoulos: I’m not sure this problem really exists, but even if it does, usually these kinds of problems take care of themselves, in the same way they do in broader disciplines of chemical engineering. If we try to interfere, then we may introduce a lot of factors that will upset the students. Stuart Cooper: I don’t like to come to Dan’s defense, but I have an observation. We’ve never required our Ph.D. candidates at Wisconsin to take
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a certain number of chemical engineering courses. Recently, for a variety of reasons, we examined the statistics of what our Ph.D.’s were taking on the way through. We concluded that they should be taking more courses in the department, regardless of the area. Now we have the beginnings of a core requirement, which I think will resolve the concern about specialization. Edwin Lightfoot: The reason that this happened is not the highly specialized nature of research. The reason it happened is the pressure to get money and the tendency of major professors to push their students to spend more time on research and less on course work. That’s the real culprit these days. Robert Brown: Were they taking a sufficient number of courses, but outside the department, or were they taking an insufficient number of courses? Edwin Lightfoot: There is not a sufficient number of courses inside our department at the upper graduate level. Stuart Churchill: I’m impressed with our doctoral students who work in this area for Doug Lauffenburger and others. I attend their oral exams, and I understand their language, so they have not lost the ability to communicate with traditional chemical engineers. They still can speak in terms of transport, thermodynamics, and so forth. In this environment, what Dan is worrying about isn’t going to happen. The converse is also true. A large fraction of my early doctoral students are now in bioengineering, although I don’t take any credit for that. David Hellums, Peter Albrecht, and Irving Miller were all students of mine. They started their careers in something else and then moved into bioengineering. As long as we don’t build too high barriers, this is a nonproblem.
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solutions via genetics to solve it. Alternatively, we can seek solutions via traditional or innovative chemical processing. It’s imperative that we train our students to appreciate the biology, on the one hand, and to understand the chemistry, on the other. Most important, we need to train our students and the people in our laboratories to understand and contribute to a multidisciplinary effort. This is one of our biggest challenges, one that I don’t think we’ve addressed adequately thus far. My third observation is that, when looking at the range of processes for handling proteins that have evolved recently, two technologies dominatefiltration and adsorption-though occasionally other methods are used. These are the domain of the chemical engineer. In two decades, we’ve done a reasonable job of understanding the fluid dynamics of processes such as ultrafiltration and microfiltration. Yet, the chemistry of filtration processes is poorly understood, i.e., the interaction between proteins and the surface of the filter and between the protein molecules and other particles that bind to the surface. Consequently, there are no predictive models for filtration processes, despite the significant amount of modeling that’s been done. Second, adsorption processes such as chromatography are critical to this industry. Again, our understanding of protein interactions with the surface and with each other is weak. Our understanding of the alternatives to these technologies, such as extractive processes, is also poor. We need to better understand both the alternatives and the fundamental chemistry of the process. Lastly, process synthesis is important in this field. The biologists dominate process synthesis in the recombinant DNA and protein manufacturing business. What limitations prevent chemical engineers from making contributions? There are two: an almost complete absence of predictive models based on fundamentals and a poor understanding of the physical and chemical properties of biological materials. These issues need to be addressed in both teaching and research. Gregory Stephanopoulos: Jay Bailey underlined the enormous opportunities for chemical engineers in biochemical engineering. We must answer the question, what can chemical engineers do here better than biologists? One example is introduction of rate processes in describing biological systems, since biologists probably are not going to do it. They are also not interested in applied biology, represented, for example, by solving the problem of hemoglobin synthesis that Jay mentioned. Does a chemical engineer require specialized training to work in molecular biology? Yes, but we do have examples of chemical engineers trained to do gene splicing. Jay mentioned one, and we have others at MIT. The important point is that these students on their own initiative learned gene splicing by talking the professors into letting them take these laboratory courses. About a
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year later, these students were producing results by putting a gene to do something useful into a microorganism or taking out a gene that the organism does not need and that we don’t want. This technology has been around for 10 years, but biologists have not applied it to the kind of problems that we are interested in. We need courses in this area. The limitation is not the eagerness of our students nor their capacity to absorb the material. But can we supply them with the tools and the courses that they need to assimilate these new concepts and techniques? It won’t be easy, because there are not many chemical engineering faculty trained in this area, and these courses are very expensive. My final point concerns the single most important development that brought about the explosion in biological sciences-the development of techniques to separate and accurately characterize proteins and other molecules that exist in the cell. This key capability enabled the discovery of restriction enzymes and other phenomena. These separation methods have been mainly physical and physicochemical techniques, not involving organic chemistry. Biologists failed as long as they tried to accomplish these tasks with organic chemistry. Gel chromatography and blotting techniques led to these results. We have an opportunity to improve these techniques, and they are the prototypes of processes by which proteins or other macromolecules eventually will be separated on a large scale.
Edwin Lightfoot: I have a few remarks on topics that may have been missed. First, we can divide biotechnology into the areas of bioprocessing, which is truly a chemical engineering activity, and metabolic engineering, where we’re concerned with the details of the living organism. Both of these have big opportunities for us. I’ll begin with an issue related to Art Humphrey’s plant cell culture example. In the early days of penicillin production, it was found that you could take molds that normally grow on the surface of water, or on wet surfaces, and submerge them into a deep tank where they would still grow. The big problem was to supply oxygen to them, because oxygen has a low solubility in water. Small submerged fermentation cultures have dominated world wide biotechnology ever since, but they aren’t suitable for a lot of purposes. A classic example is mold spores, which are not normally formed in submerged fermentation cultures. This suggests going a different route. One can find some good leads in looking at the diffusion capacity of water and air. Air will transport oxygen 500,000 times better than water. Thus, molds and other plants grew in air originally for a good reason. Consequently, there’s increasing interest in solid substrate fermentations, of which the prototype is the malting industry, where air is blown through a damp, not wet, solid, granular mass. This method has several advantages. It is the basis
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for a great many foodstuffs, such as soy sauce. It can also be used for processes on the horizon, like biopulping of wood, where wood chips are inoculated with molds, and so forth. Radical changes in fermentation technology can solve some basic problems and produce substantially increased effectiveness. The essence of living systems is the complex reaction networks that produce life processes, and those are a natural place for chemical engineers to get involved. We can’t beat the biochemists on their own ground, because they’re trained to handle these multitudinous biochemical reactions and to learn something about their interrelationships at a qualitative level. Until recently, few of them addressed systems aspects. There are three that I think are particularly important. One is getting material balances when you have thousands of species present. It’s sometimes important to find out how many reactions are being used and at what rates. Charlie Cooney has pioneered that area. The most recent work I’m aware of is from EastmanKodak; John Hamer and Jim Liao have used singular value decomposition techniques to get relations between metabolites. By doing that they can find out when the fermentations are off course, and perhaps even when they become contaminated, quite early. The second is sensitivity analysis, or how to decide what enzyme out of hundreds you want to increase the activity of. The biochemists call that control analysis. It’s an important area that I think Jay Bailey touched on. The final one is dynamics, and it is important to realize how many diseases are essentially dynamic and have much in common with poorly controlled manufacturing processes. Diabetes is one of the most interesting to me at the moment. The whole purpose of insulin management is to minimize the time-average sugar levels in the blood without going below a lower level too often, resulting in insulin shock. That’s similar to problems in a manufacturing process, because you don’t have access to all of the information you need. All you can do is measure sugar levels at intervals that are too far apart to be really controlled. That gets pretty close to the heart of modern chemical engineering. Clark Colton: I have comments in three areas. The first comment concerns the motivation for research in biomedical areas. I believe the primary factor is that this field is rich in intellectually challenging issues that provide good problems for training chemical engineers. As Channing Robertson pointed out, living organisms are complex bioreactors. In animals, one finds that life processes are determined largely by transport phenomena, thermodynamics, and reaction kinetics, as well as an extraordinary diversity of molecular and supramolecular interactions. In his review of the intellectual origins of chemical engineering to be presented at the Convocation, Skip Scriven focused largely on our growth out of industrial chemistry. Although the lineage is far less direct, one could make a case that the intellectual
Bioengineering
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forebears of modern chemical engineering include some of the physicianphysiologists of the 19th century. These scientists set out to show that the functions of organisms could be explained on the basis of the physicochemical laws of nature. One example is Jean L. M. Poiseuille, who was interested in the circulation of blood through the cardiovascular system. His objective, to test the then-popular hypothesis that blood flow derived from the motive force of red cells, led him to experiments on pressure-flow relationships with pure fluids in fine glass capillary tubing, resulting in the classic law that bears his name, published in 1840. Poiseuille’s experiments were conducted with great care; his measurements of the temperature dependence of what is now called viscosity agree to within 0.5% of modern values for water. Perhaps the quintessential example of these researchers is Adolph E. Fick, who began his studies in physics and mathematics, switched to medicine, and eventually became a professor of anatomy and physiology. In the course of his career during the second half of the 19th century, Fick’s diverse contributions included molecular diffusion in liquids and porous membranes, solid mechanics applied to bone joints and muscles, hydrodynamics in rigid and elastic tubes, thermodynamics and conservation of energy in the body, optics of vision, sound, and bioelectric phenomena. We know him for the differential equations he developed ( 1855-1 857), known as Fick’s laws of diffusion, that are taught to all undergraduate chemical engineers. He is at least as renowned in the medical profession for another law, Fick’s law of the heart. In 1870, he developed a method for calculating cardiac output from measurements of oxygen consumption and of oxygen concentration in the venous and arterial blood. His principle is nothing more than a material balance for oxygen around the pulmonary circulation! My last example is Adrian V. Hill, who received the Nobel Prize for Physiology and Medicine in 1922 for his work on the production of heat and lactic acid by muscle. In 1928, he published an extensive paper on mathematical aspects of reaction-diffusion problems associated with diffusion of oxygen and lactic acid through tissue. His paper presaged the classic works of Thiele, Damkohler, and Zeldovich a decade later. I could cite other examples, notably Hermann von Helmholtz, but I think my point is clear. A secondary motivation for research in biomedical areas is the significant growth in hiring of chemical engineers by the health care industry in the past decade. For example, artificial kidneys are now used to treat more than 300,000 patients worldwide, and commercial sales of associated products are more than $1.5 billion per year. In the next decade, we are likely to see other new therapies open up similar markets, possibly with implanted devices. Development of these new technologies will require a much better understanding of the interaction of materials with biological macromolecules, cells, and tissues, some of which Channing referred to.
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My second comment concerns labels in bioengineering. There was a time when those in biochemical engineering were concerned exclusively with production of materials by fermentations of microorganisms and those in biomedical engineering with physiological processes and medical devices. With the advent of recombinant DNA technology, especially its application to animal cells, and the growth of “biotechnology,” a term which has been applied to a multiplicity of disparate areas, the distinctions have blurred. For example, some areas of research, such as animal cell bioreactors, interactions between synthetic and biological materials, and separation processes for proteins and cells, fall within both provinces. Likewise, the common knowledge base required in these areas of bioengineering has broadened to the point of substantial overlap, encompassing such fields as biochemistry, biophysics, cell biology, and immunology. My third comment echoes the point made by Jay Bailey, that our undergraduates should be exposed to biology. My position is not based on its utility for later research or its role in professional training. Rather, I believe the time has come that individuals cannot consider themselves scientifically literate without some understanding of developments in biology. The revolution in the biological sciences that began in the 1960s has proceeded at a rapid pace, and the rate of development of new knowledge and understanding shows no signs of abating. We pride ourselves on being the most broadly trained of engineers, with backgrounds in mathematics, physics, and chemistry. I suggest that biology be added to that list, as it should be for any educated scientist. Sheldon Zsukoff: There’s an issue in the production of pharmaceuticals that hasn’t been brought up by the speakers, yet it’s pertinent to the changing character of chemical engineering, and that is regulation. Anytime you introduce a new material that gets into the human body, you need the approval of the Food and Drug Administration. If you do experiments on a small scale and get your approvals from the agency, those approvals are not only for the material that you’ve produced but also for the process by which you produced them. If you change your process when you go commercial or produce larger lots of the material, you have to go through the approval process again. Timeliness in getting the product out to the marketplace is crucial in this business, as in many others. It’s important for chemical engineers to be involved early so that when FDA approval is obtained, you know that you have a process that is scalable to commercial size and will turn out a product having the same properties and efficacy as the material produced at small scale. Daniel Wang: Bioengineering is really about practicing the fundamentals of chemical engineering. We do things well quantitatively, whereas biolo-
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gists don’t. Take Sheldon Isakoff’s point about the FDA and clinical trials. Do you realize that it costs more to put a product through a clinical trial than to make it? It’s about $100 million to $150 million per product, and one out of three is successful. Any big company will have to spend at least $100 million to get out one product. Let’s look at pharmacokinetics and the work done with compartmental analysis. We should become involved with the biology of clinical trials in a quantitative way. Can we do more than just say the profile in compartments of the body follows a certain pattern? Engineers have to start looking into this other side of regulatory activities. We also totally lack a leadership role in the proper places, such as Washington. Why does the FDA ask us questions about the process? They don’t know what the three-dimensional structure is. The covalent structure is easier to define, the secondary and tertiary structures are more difficult. The only way they can be sure of what’s happening is to make certain our processes are identical, because all else is unknown. Why are the biologists doing everything? Because they have a presence there. We have to make our own destiny. One example is involvement with clinical trials. We need to do more, because we can do things in a quantitative way. Edward Merrill: I feel like Don Quixote against the windmills with respect to blood viscosity, the study of which, as Clark alluded, began with Poiseuille, a French physician in the 1700s. Would you believe that today, if you go through the index of Harrison’s Principles of Internal Medicine, you won’t find a single reference to the viscosity of anything, including blood, so the internist has no idea of the concept? For 25 years, I’ve been talking to physicians about the importance of viscosity, and they look at me with glazed eyes. We sometimes have to work hard on our colleagues in other disciplines to bring their attention to what we would have thought was an important concept. My second comment is apropos of Channing Robertson’s remarks, which I admired. In regard to polymers, it seems to me that the time has come to adopt again a unifying approach like that of Charles Tanford, professor of biochemistry at Duke University, who wrote the book Physical Chemistry of Macromolecules comparing biopolymers with synthetic polymers. In polymer synthesis, let’s look at the synthesis of peptides, amino acid by amino acid, and the desynthesis of peptides by sequencing, and bring this into our curriculum. William Deen: I’d like to emphasize a point that came up in Clark’s remarks and Channing’s remarks. That is, the exchange of information between chemical engineering and medicine or the life sciences is in both directions. Several examples were cited of how we can affect medical practice
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through development of devices or novel therapies. We can also affect medical education by contributing to its scientific base. Further, we can learn from developments in the medical sciences. Clark pointed out two very nice historical examples, Poiseuille’s law and Fick’s law. Another more recent example is the concept of carrier-facilitated transport, which originated to explain special properties of biological membranes and has since found application in chemical separations processes. At least until recently, membrane biophysicists have been way ahead of engineers in understanding the physics of transport through membranes. That understanding provides a basis for modern membrane separations, including ones becoming important in biotechnology. It’s important for us as a profession to maintain this window, this area of focus, even though the health care industry will probably never provide a large number of career opportunities for chemical engineers. As Clark mentioned, the health sciences provide interesting problems for research, and the exchange of information occasionally inspires new ideas on how to accomplish a chemical transformation or separation.
Thomas Edgar: What percentage of B.S. chemical engineers would you estimate go into the health care, pharmaceutical, or biorelated industries today, and what percentage do you forecast 10 years from now? Bill Deen made it sound like there are not that many opportunities. I am not talking about Ph.D.’s, just B.S. engineers. Clark Colton: In the past few years, there has been a marked increase in hiring of graduate chemical engineers by the pharmaceutical companies in the bioprocessing area and, to a smaller extent, by the health care companies. I believe there has also been an increase in hiring of B.S. chemical engineers, although I don’t think the demand will ever be gigantic at that level. Thomas Edgar: I’m just trying to get perspective. Larry Thompson showed us a curve of engineers hired by the microelectronics industry, and I’m trying to understand the relative magnitude of demand here. Edwin Lighrfoot: Tom, you’re being unfair because you’re not counting the Ph.D.’s, and that makes considerably less people. It takes a fair amount of specialization in an area like this. Thomas Edgar: I’m not being unfair, I’m just asking a question. L. E. Scriven: It’s quite evident in Minneapolis, which is the home base of General Mills, Pillsbury, International Multifoods, and so on, that the process food industry has absorbed thousands of chemical engineers. They may not be doing the kind of biotechnology that you’re speaking of, but their industry certainly is an important consumer of chemical engineers. The
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conversion from food technologists to chemical engineers has been made. There appears to be a similar trend in other agriculture-based process industries. Arthur Humphrey: If you lump all of the B.S. students who go into medicine, veterinary science, and dental science, and add all of those going into the health care, pharmaceutical, food, and agricultural-based industries, you get up to almost 25% of the chemical engineering profession. You have to define food and agriculture on a very broad base. My own concept is that this field is probably going to utilize 25 to 30% of the chemical engineers when it reaches an equilibrium. James Wei: The AIChE had a survey on that subject. I think that the food industry is hiring 1.7% so far. Daniel Luss: I want to raise an issue that concerns the training of chemical engineering graduates who conduct research in biochemical engineering. Every major department now has a research program in biochemical engineering, and they attract many of the most talented students who enter the graduate programs. The proper training of chemical engineering students carrying out research in this area requires that they take a large number of courses in the biological sciences. Thus, if they work in a traditional chemical engineering area, a large fraction of their training will not be utilized. Clark Colton: I disagree. It’s true that students doing graduate research in bioengineering may have to take some specialized subjects in the biological or medical sciences, but this is no more limiting than for any of the other relatively new areas we’ve been discussing. It’s important that students are exposed to sufficient graduate chemical engineering course work and that there be substantial chemical engineering content in their research. With this proviso, these students don’t lose the breadth of their undergraduate training for applications in industry. The limitations are greater if one goes into academia, because one’s thesis often fixes one’s research area, and it’s difficult to change fields, especially as an assistant professor. When I started out, there were few if any industrial jobs related to the research of my students. That situation has changed today. My earliest students either went into teaching or they went into industry. Those who went into industry did the same things that other chemical engineers did because they had appropriate training and were able to use it. Daniel Luss: Several faculty members working in this area insist that their students take a large number of courses in the biological sciences. I’m told that it’s essential for anyone who wants to do research in this field. I raise the question whether it’s the best training for a student who will not be
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employed in this area. It’s clear that the number of available teaching positions in chemical engineering departments for these graduates is declining, as most departments already have young faculty members for biochemical engineering. As a consequence, most of the graduates may have to find industrial employment, and at present the biochemical industry does not hire very many such graduates. Clark Colton: Whether there is a problem depends on the environment the student is in and the nature of departmental requirements. In our department, all doctoral students must pass a qualifying exam that is based on the core areas of fluid mechanics and transport, thermodynamics, and kinetics and reactor engineering. Although there are no formal course requirements for the Ph.D., in practice virtually all entering students enroll in the associated core graduate subjects. Students are also expected to take a reasonable number of additional graduate subjects in the department. There’s a formal requirement for a minor, and it’s in this context that most students doing bioengineering research take biology or medical science subjects outside the department. Students who receive this kind of exposure don’t lose their chemical engineering identity or capabilities. They can function well in industry. If anything, they enrich the profession.
Edwin Lightfoot: I have two students in this category. The first started in
separations, and he’s taken a lot of biology, but what he’s really working on is NMR techniques. He’s going back to the basic quantum mechanics to study NMR techniques. The other student is working on diabetes, and she’s taken advanced processing control courses because this is a control problem. Alan Hatton was one of these to a degree, as was Abraham Lenhoff, now at Delaware. These people have done very well in fields that are quite different from where they started. This is a bum rap. Robert Cohen: I believe this is more than semantics. The problem that Dan brings up is contained in the way he discusses it. If you think of graduate training, the word “train” is what I object to. Graduate education is different from job training, and if you’re picking a good problem, there’s educational value in that, and the specific field is more or less irrelevant. Gregory Srephanupoulos: I’m not sure this problem really exists, but even if it does, usually these kinds of problems take care of themselves, in the same way they do in broader disciplines of chemical engineering. If we try to interfere, then we may introduce a lot of factors that will upset the students. Stuart Cooper: I don’t like to come to Dan’s defense, but I have an observation. We’ve never required our Ph.D. candidates at Wisconsin to take
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a certain number of chemical engineering courses. Recently, for a variety of reasons, we examined the statistics of what our Ph.D.’s were taking on the way through. We concluded that they should be taking more courses in the department, regardless of the area. Now we have the beginnings of a core requirement, which I think will resolve the concern about specialization. Edwin Lightfoot: The reason that this happened is not the highly specialized nature of research. The reason it happened is the pressure to get money and the tendency of major professors to push their students to spend more time on research and less on course work. That’s the real culprit these days. Robert Brown: Were they taking a sufficient number of courses, but outside the department, or were they taking an insufficient number of courses? Edwin Lightfoot: There is not a sufficient number of courses inside our department at the upper graduate level. Stuart Churchill: I’m impressed with our doctoral students who work in this area for Doug Lauffenburger and others. I attend their oral exams, and I understand their language, so they have not lost the ability to communicate with traditional chemical engineers. They still can speak in terms of transport, thermodynamics, and so forth. In this environment, what Dan is worrying about isn’t going to happen. The converse is also true. A large fraction of my early doctoral students are now in bioengineering, although I don’t take any credit for that. David Hellums, Peter Albrecht, and Irving Miller were all students of mine. They started their careers in something else and then moved into bioengineering. As long as we don’t build too high barriers, this is a nonproblem.