MIT Reports to the President 1994-95

Biotechnology Process Engineering Center

The Biotechnology Process Engineering Center (BPEC), an interdepartmental center at the Massachusetts Institute of Technology, is a pioneering program in education and research for the biotechnology industry. BPEC, established in May 1985, is funded by the National Science Foundation (NSF) under the Engineering Research Center Initiative. Nearing an end to the first phase of this center's NSF support, the center reapplied for further funding. Through a highly competitive reapplication process, the NSF awarded the BPEC an additional 11 years of funds effective September 15, 1994 through September 14, 2005.

As an interdepartmental center, the BPEC reports to the Dean of Engineering. The Director of the center is Daniel I.C. Wang, Professor of Chemical Engineering. Three associate directors help in the operations of the center. The associate directors are: Charles L. Cooney, Professor of Chemical Engineering and Associate Director for Industry; Gregory N. Stephanopoulos, Professor of Chemical Engineering and Associate Director for Research; and Anthony J. Sinskey, Professor of Biology and Associate Director for Education.

The mission of the BPEC is to develop advanced manufacturing ideas and technologies, to ensure US competitiveness in the production of therapeutic proteins by creating a new breed of professionals. To achieve this goal, the center focuses its efforts through education, research, and industrial involvement.


A cross-disciplinary team consisting of biologists, chemists, and chemical engineers executes the research in two thrust areas: 1. Therapeutic Protein Production: Quantity and Quality; and 2. Therapeutic Protein Aggregation, Stability, Formulation and Delivery. Cross-disciplinary educational and research collaborations are especially important components within the center's activities.

A team of 11 faculty members participated in the center's activities from July 1, 1994 through June 30, 1995. They are from the Departments of Chemical Engineering (School of Engineering), Biology, and Chemistry (School of Science), the Department of Chemistry, Iowa State University, and the Department of Chemistry at Purdue University. Undergraduate and graduate students, postdoctoral fellows, visiting scientists, and industrial associates are integral participants in the center's activities.

Statistically reporting, 228 personnel took part in the center's research activities during fiscal 1995. This figure comprises 30 MIT Undergraduate Research Opportunities Program students (UROP); sixteen MIT Undergraduates working on course-related projects; twelve non MIT undergraduates from 11 different Universities who participated in the center's NSF Research Education for Undergraduates Program (REU); eighty-two graduate students from four departments; four technical assistants; forty-nine postdoctoral associates/fellows; nineteen visiting scientists, engineers, industry researchers, four other administrative personnel and 12 faculty.

Funding sources are explained as follows. The NSF provides the major financial support for BPEC personnel. The National Institutes of Health (NIH-NIGMS) provide additional support for graduate educational activities for the MIT students. In addition, unrestricted funds have been secured from outside sources. The center received industrial donations as contracts, fellowships, equipment, and software.


The BPEC is committed to increasing the number of women and minorities in its programs. Our success is dependent on the type of applicants. To assure many applicants for the National Institutes of Health Interdepartmental Training Grant, we have formed a minority recruitment committee. Specifically, in March 1995 recruitment took place off-campus at the 21st Annual National Convention of the National Society of Black Engineers in Detroit, Michigan.


The goals of BPEC's educational programs are to ensure the training will affect undergraduates, graduates, post-doctoral and industrial personnel. Our visions in the educational programs are to incorporate biotechnology principles into our existing courses through modifications and the teaching of interdisciplinary courses resulting from the research thrusts of the BPEC. Combining our visions and goals, our educational program will achieve an integrated view of biotechnology processing; an atmosphere of team work with cross-disciplinary interactions; an exposure of our students to the real world of industrial biotechnology; and a new breed of professionals for industry, university, and government.

The BPEC faculty in fiscal 1995 introduced six new courses (three undergraduate courses; "Process of Change," "Biotechnology: Engineering of Macromolecules," and "Integrated Chemical Engineering"; two graduate courses; "Capillary Electrophoresis," and "Principles and Methodologies of Metabolic Engineering"; one industrial course; "Analytical Biochemistry in Process Monitoring and Validation"). The center's funds supported each teaching assistant's stipend. One new course, "Integrated Chemical Engineering: Biochemical Engineering," was introduced to meet the desires of our undergraduates in learning bioprocess engineering. This is a core course for undergraduate chemical engineers where biotechnology and biochemical engineering are integrated using the principles of chemical engineering. In addition, workshops where the center's students and faculty can interact on-campus and at other universities and industrial sites were given by the BPEC. The center continued to hold two very active undergraduate programs during Fiscal 1995. The programs are the Undergraduate Research Opportunities Program (UROP) and the Research Experience for Undergraduates (REU). The NSF program funded the REU program separately, and as mentioned above, supported 12 non-MIT students. We continued our seminar program entitled, "UROP and REU Seminar," in which the undergraduates presented their research experiences to the center's personnel weekly. A BPEC team gave a workshop series on presentation skills to the Center's undergraduates. The students were provided with basic research and presentation tools as part of the educational program. In addition, BPEC instilled cross-disciplinary and team research in each student. Another seminar series on Scientific Integrity was successfully introduced for the first time during the summer of 1994. All BPEC students were invited to participate. MIT and Industrial participants made presentations. We have already planned to repeat this series for fiscal 1996.

Outreach activities in the current year include participation of faculty from other universities along with their students in the Center's research. Outreach activities by the BPEC included the research participation by one student from the Wellesley Education Cooperative Program for High School Students. Tours were given to 19 under-represented minority students and teachers from the Boston and Cambridge, MA schools. Since the BPEC has two Co-PI's (Professor C.S. Lee, Iowa State University and Professor F.E. Regnier, Purdue University) collaborating with our Center, these individuals brought their students and postdocs to the BPEC during the fiscal 1995 summer months.

At the graduate level, the Center continued to bring interdisciplinary ideas into the course teachings. BPEC successfully completed the sixth year on the NIH Interdepartmental Biotechnology Training Program (BTP) which was officially inaugurated in 1989. Funding for this program is provided by the NIH-NIGMS and was renewed for an additional five years of funding effective July 1, 1994. This program is organized to train 21 Ph.D. students to become providers for the scientific and engineering talent and leadership needed to maintain the growth phase of the new industry, and to educate the next generation. Twenty-five faculty members from MIT are involved, representing the Departments of Biology, Chemistry and Chemical Engineering. Professor Daniel I. C. Wang, the center's director, is also the director of this program. Professor Jonathan A. King, a professor in the Department of Biology, is program chairman. The BPEC graduated 15 Ph.D. and four M.S. candidates. Nearly 75% of our graduates enter industry. At a time when industrial hiring has decreased in other disciplines, we have not found this to be the case for our graduates because of the training that we have provided in biotechnology process engineering.

Industrial educational activities were achieved through the Special Summer Course Program at MIT. In Fiscal 1995, six special summer courses under the auspices of the BPEC were presented. BPEC faculty taught 15 undergraduate courses, 10 graduate courses, six industrial courses on site; one mini course off site; and one workshop on site.


The vision of the Biotechnology Process Engineering Center (BPEC) is to establish, through research and education, the advanced manufacturing concepts and processes that will ensure the competitiveness of the US biotechnology industry. To achieve this goal, a strong cross-disciplinary team consisting of biologists, chemists and chemical engineers has been formed to execute its programs. The research thrusts of the BPEC have continued to focus on the original vision: the production of complex therapeutic proteins.

The research thrusts in this Center have been directed to those areas where generic needs have been expressed from the industrial manufacturing sectors. Specifically, the ability to achieve high concentration (quantity) accompanied by high productivity (rate) has become one of the Center's thrusts. In addition, product quality and uniformity has been another thrust being developed by the Center. Bioanalytical techniques became a natural interface for the increased protein quantity and quality in animal cell systems. The second major thrust is to ensure the stability, formulation and delivery of the therapeutic protein during processing and delivery. Here again, cross-disciplinary interactions have been executed to meet this goal.

The major impact on the research culture has been the instilling and executing of its activities through cross-disciplinary interactions. Several examples are presented to illustrate this change in the research culture of our students. The first example is a three-level cross-disciplinary interaction between biology, chemistry and chemical engineering. This project's goal is to increase the quantity and productivity of complex therapeutic protein using animal cell cultivation. This represents an excellent example where the integration of molecular biology with chemical engineering to solve jointly the problem of increased quantity and productivity of therapeutic protein production. The mechanisms of cell death which decrease both the amount of protein produced and the rate of production are being addressed through molecular events (apoptosis) and kinetic analysis of end product inhibition. These combined efforts along with real time process monitoring from bioanalytical chemistry allow the operation and control of the bioreactor to achieve the final goal.

The second cross-disciplinary collaboration again includes these disciplines: biology, chemistry and chemical engineering. The issues addressed relate to bioprocess operations on the protein quality with respect to macro- heterogeneity and glycoforms. The approaches to this problem involve the three disciplinary inputs. The goals and achievements include both in vivo synthetic rates of protein synthesis and protein processing, which are then translated to the bioreactor's environment to ensure reproducibility and improved protein quality.

The third cross-disciplinary project is a three-level collaboration (biology, chemistry and chemical engineering). The issue addressed deals with protein-protein interactions during folding and refolding. The molecular biology tools in addressing the in vivo protein folding using site directed mutagenesis to derive folding (aggregation) mutants are coupled with engineering studies on the in vitro kinetics and equilibria during refolding. The bioanalytical chemists work collaboratively to develop advanced monitoring techniques for detecting folding intermediates, all of which, led to a better understanding of both the in vivo and in vitro folding pathways. These studies will allow us to devise and design efficient and improved protein refolding processes.


The industrial interactions during fiscal 1995 were achieved through both knowledge-based and technology-based advances. Industrial collaborations and technology transfer are important goals of the center. In 1986, our Industrial Consortium Program was established with a membership of 38 companies. The BPEC Industrial Consortium Program has 59 companies representing all sectors of the biotech industry. The consortium and other companies made 72 visits to this ERC to gather research and other information. Our faculty presented 31 industrial seminars reaching an attendance of 1,700. Lastly, we held our annual symposium in January 1995 with the attendance of 430 people which mostly were from industry. Technology transfer interactions were achieved through 42 collaborative research projects. We transferred sixteen specific types of technologies to various companies ranging from products to industry. Four industrial personnel performed collaborative research at this Center.

A new initiative in cross-disciplinary research with direct involvement from multiple companies was started during fiscal 1995. This is the "Cell Culture Optimization Consortium." The planning of the research is achieved through the members of the Consortium. The elements of the collaborations are to address long-ranged generic problems which are relevant to industry. We also want to ensure a constant exchange of information and technology exchange. The goals are to achieve high product concentrations and increased productivity using both the BPEC and the Consortium companies as test-beds to demonstrate the generic solutions from this collaboration.

The planning and assessment of the Center's research, education and other activities are achieved through the Industrial Advisory Board. Due to the nature of our research in the years to come, the past Industrial Advisory Board was dissolved in December, 1994. The past Board had been in place for the past five years. It was our belief that changes in our Center warranted new insights to our research and other activities. Therefore, a new Industrial Advisory Board was established in January 1995. The new Board is smaller (eight members) and all have expertise in the research thrusts in the Center.

As part of BPEC's effort to foster technology transfer, it has established an Industrial Consortium Office. Its responsibilities include coordinating company visits; distributing research abstracts, published papers, and student theses; organizing workshops and symposia; and maintaining a database of BPEC research projects. This office works closely with the BPEC faculty, BPEC students, the MIT Industrial Liaison Program, and the MIT Technology Licensing Office to serve company needs.

The center has been quite productive during fiscal 1995. Personnel have produced 200 publications, given 98 presentations, participated in 31 industrial and 46 university seminars, produced 19 theses, and met with visitors from 72 different US companies. Many of these visits led to collaborations between the BPEC and the company.

Daniel I. C. Wang

MIT Reports to the President 1994-95