The Interface Of Biology And Chemical Engineering

Chemical engineers and biologists say that collaborations between their disparate disciplines are beginning to bear some valuable fruit, not just in the applied field of biotechnology, but also in understanding basic cellular mechanisms. Yet those who are currently working at this cross-disciplinary interface say the challenge today is to get these two scientific cultures to interact. One way to bridge such a gulf is to have a meeting and invite interested members from each discipline to attend--which is exactly what has recently happened. "Research Opportunities in Biomolecular Engineering: The Interface Between Chemical Engineering and Biology" was convened in Washington, D.C., on December 7-8, under the auspices of the National Institute of General Medical Sciences (NIGMS). Says George Georgiou, a chemical engineer at the University of Texas, Austin, who co- chaired the meeting: "The idea of the meeting, in my mind, was to make more people aware of the interface that already exists and attract them to work at that interface and to build momentum for federal support of this work." Georgiou, for instance, has crossed the disciplinary barrier to collaborate with UT microbiologist Charles Earhart as well as fellow chemical engineer Joseph Francisco. Together they have produced Escherichia coli bacteria that instead of excreting proteins--as is the usual case in the biotech industry--anchor important enzymes, such as cellulases, to their surface (J.A. Francis-co, et al., Bio/Technology, in press). At the December meeting, Georgiou attempted to define "biomolecular engineering," the new term that's been coined to describe the emerging body of work coming from the interface of biologists and chemical engineers. "It may be argued that biomolecular engineering is applied biology or, more precisely, applied molecular biology to distinguish it from areas of applied research related to organismic biology," he told the attendees. "Yet, this definition is inadequate and self-limiting. It is best to think of biomolecular engineering as an area of scientific endeavor which is characterized by the following elements: emphasis on the analysis of model systems of obvious significance to medicine and biotechnology; the synthesis of information and research approaches from disciplines such as cellular physiology, genetics, physical biochemistry, and chemical engineering; and the translation of biological information into a quantitative framework." The translation of the biological into the numerical seems to be the most valuable element of this interface of fields, according to many researchers who attended the meeting. "Chemical engineers all have a certain quantitative bent that exists in their training that doesn't exist in the training of biologists," says Jonathan King, a highly regarded molecular biologist at the Massachusetts Institute of Technology who works closely with chemical engineers. About seven years ago, he says, he was looking at problems associated with protein aggregation. The biotechnology industry was just beginning to scale up production of its products but was encountering problems of proteins that have the intended amino acid sequence but don't fold up properly and hence aren't bioactive. King says he found few biologists or biochemists who were interested in or capable of working on these "scrambled egg" messes of misfolded proteins. "Initially, we were only able to talk to chemical engineers," he says. "They're used to dealing with polymers, and the problems you get when you scale up [production] are their stock and trade." He found it was a mind-set problem that hindered his interactions with biologists on this problem. "Biologists want to win Nobel Prizes and chemical engineers want to build factories. They have very different standards of achievement," he says. Douglas A. Lauffenburger, a chemical engineer at the University of Illinois, Urbana-Champaign, chaired a session on cell and tissue engineering at the December meeting. He is excited by the possibilities the melding of these two disciplines can engender. "An engineer is taught over and over again to think quantitatively and in terms of dynamics and kinetics, while a biologist is taught how to think descriptively. It's incredibly complementary. The best work in biomolecular engineering is going to be done at the interface and by two people, instead of one." But bringing these two scientific cultures together is a continuing challenge, says King. MIT's Biotechnology Process Engineering Center, funded by the National Science Foundation, has helped biologists and engineers coalesce. Janet Westpheling, a microbial physiologist at the University of Georgia in Athens, says the best physiologists are among chemical engineers because "they're interested in directing carbon flow from one metabolic pathway to another." She explains: "It's better for me to make contact with a chemical engineer who knows what he's doing than trying to be a mediocre chemical engineer. But biologists are going to have to make an effort to learn the language of chemical engineering." Before trying to make contacts, she recommends reading the highly cited textbook Biochemical Engineering Fundamentals (New York, McGraw- Hill Publishing Co., 1986), written by California Institute of Technology chemical engineer James E. Bailey. One problem that Westpheling and others note is that making contacts is difficult because chemical engineers and biologists rarely attend each other's meetings and don't publish in or read the same journals. That's why the NIGMS biomolecular engineering meeting was so useful, they say. It was a gathering place for biologists and chemical engineers--basic researchers as well as industry-based scientists. Lauffenburger says these cross-cultural conclaves are vital as ways of getting in touch with other researchers interested at working at the interface of disciplines. In fact, it was a workshop four years ago that sparked what has turned out to be quite a valuable collaboration. He says the organizers of the "Workshop on Mechanisms of Protein Trafficking," held at the University of California, Davis, in March 1988, "went out of their way to bring a diverse group together." At Davis, he met cell biologist Steven Wiley from the University of Utah Medical Center in Salt Lake City. Each man was quite familiar with the other's work, but they had never met or talked. Wiley says he is best known for a paper in Cell that laid out a quantitative model for how the epidermal growth factor receptor works (H.S. Wiley, et al., Cell, 25:433-40, 1981). A more detailed paper appeared the next year in the Journal of Biological Chemistry, and has been his most popular work, garnering 180 citations as of mid-1992, and reaching its peak at 30 citations in 1990 (H.S. Wiley, et al., JBC, 257:4222, 1982). To develop this model, he took what was then known about the molecular "parts" of the EGF receptor and the rates at which they functioned, and he then built a mathematical model that could predict how the cell would respond if certain parameters were changed, such as concentration of hormone or number of surface receptors. While this paper garnered a lot of attention when it was published, as time rolled on and research progressed on EGF receptors, more "parts" had to be added to the model. That's where his mathematical abilities ran out. And that's also when a lot of biologists became increasingly skeptical of the value of this mathematical modeling approach to receptor study. "Then I met Doug Lauffenburger, and suddenly I had a kindred soul," he says. Together they've been able to advance this modeling approach to understanding the basic science of receptor function (H.S. Wiley, et al., JBC, 266:11083-94, 1991). "What I'm trying to add," says Lauffenburger, "is a quantitative understanding of rates and magnitudes of signals. Most people in the field are trying to identify components. Identifying components is critical but insufficient for understanding the signal because they depend on magnitudes." One use for the model has been to guide their thinking on how an excessive number of receptors leads to a transformation into a cancerous cell. What apparently is happening is these receptors choke the system that recycles them, shutting down the regulatory pathway, thus leaving the cells out of control, not overcon- trolled as might be expected. Wiley says his newest biomolecular engineering project is to attempt to develop an "autonomous bioreactor system." Under a grant from NSF's biotechnology program, he is working on a system of cell cultures that would not only produce valuable proteins-- but also supply its own growth regulators, obviating the need to supply complex and costly serums containing these factors. A project intended to bring about increased interest in work at the interface of disciplines is a book coming out this spring by Lauffenburger and coauthor Jennifer J. Linderman, also a UI chemical engineer. In the forthcoming Receptors--Models for Binding, Trafficking, and Signalling (New York, Oxford University Press) they write: "We intend this book to build a bridge between cell biologists and engineers over the ground that can be called quantitative cell biology or cellular bioengineering. Our aim is to com- municate how insights can be gained into the relationship between receptor/ligand molecular properties and the cell functions they govern, by a judicious combination of cell biology experimentation and quantitative engineering models." The bulk of funding for studies in biomolecular engineering has traditionally come from NSF, with additional money available from the Whitaker Foundation, which now has an office in Washington, D.C. (Scott Veggeberg, The Scientist, March 30, 1992, page 21), as well as from the biotechnology industry, says Michael Shuler, a chemical engineer at Cornell University. The National Institutes of Health has provided some funding in support of biologist-engineer collaborations through its Interdisciplinary Biotechnology Training Grant Program. But otherwise, grant review committees have apparently been prejudiced against anyone with a chemical engineering title, Shuler says. "Funding committees don't real-ly seem to understand the purpose of what's being done," he says, noting, however, that the December conference has probably been helpful in breaking down this bias. "There were probably people at NIH who had certain questions about the quality of science in this community, and where the interface may be," he says. "And I think they came away from this conference feeling the quality of science was very good." He says while contacts were made and grant officials--he hopes--were convinced of the value of the biology-chemical engineering interface, it will be a couple of years before it's known how effective the conference really was in terms of increased research opportunities. More funding will be critical not only because of the explosion of intellectual interest in these studies but also to take advantage of the field's benefits to U.S. competitiveness in the biotechnology sector. While NIH may try to implement more programs to encourage research at the interface, there's more than life scientist snobbery that's blocking chemical engineers' access to funding, says Marvin Cassman, deputy director of NIGMS. Chemical engineers need to examine their own biases, he says. "If you're going to do well in the NIH peer review and funding decisions, you need to submit proposals that are hypothesis- driven. This is not the way an engineer approaches a research problem," Cassman says. "Also, it's not that there are specific barriers to getting funding at NIH, but it's a mind-set that chemical engineers may not think of NIH." They instead go to NSF first rather than trying to successfully negotiate the NIH landscape, he says. Training Biologist-Engineers In addition to increased funding opportunities, engineers must be trained differently, says Jim Swartz, group leader for bacterial fermentation development at Genentech Inc. of South San Francisco, Calif. He was part of a committee, including such widely respected chemical engineers as MIT's Danny Wang and Harvard University's George Whitesides, that produced Putting Biotechnology to Work: Bioprocess Engineering (Washington, D.C., National Academy of Sciences, 1992). In this report, they call for a new paradigm for training the next generation of biologically grounded engineers. "It is important that the bioproc-ess engineers' training in the next decade have a strong background in biochemistry, molecular biology, cell biology, and genetics. That will facilitate useful communication of bioprocess engineers with the bench scientists who are at the initial discovery stage of biological product research and development," according to the report. "To implement this type of research, cultural changes in the engineering and scientific communities will be required. For example, a doctoral candidate in chemical engineering is often viewed as performing research as a single investigator when, in fact, input from multiple disciplines is essential." In Swartz's mind the ball is now clearly in the NIH court for advancing work at the interface. "I think NIH is an excellent place to foster this research." NIGMS's Cassman says his first order of business is to get the summary papers from the December meeting out in published form, sometime this spring. From there it will be up to other officials at his and other institutes whether they catch the cross-disciplinary fever and move ahead with funding new research and training initiatives.

The Interface Of Biology And Chemical Engineering

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