MIT Reports to the President 1995-96


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. The BPEC, through a highly competitive reapplication process, has been awarded an additional 11 years of funds by the NSF effective September 15, 1994 through September 14, 2005.

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.


As an interdepartmental center, the BPEC reports to the Dean of Engineering. The center's management consists of the Director, Daniel I.C. Wang, Institute Professor and Professor of Chemical Engineering. In addition to the Director, the management team consists of the Associate Director, Gregory N. Stephanopoulos, Professor of Chemical Engineering, the Assistant Director, Ms. Audrey Jones Childs, and four thrust team leaders. The thrust area leaders meet with the Director once a month to discuss the critical issues in research, financial planning, new research initiatives, and new members to the BPEC. The Thrust I leaders are Anthony J. Sinskey, Professor of Biology, and Gregory N. Stephanopoulos, Professor of Chemical Engineering. The Thrust II leaders are Jonathan A. King, Professor of Biology, and Alex M. Klibanov, Professor of Chemistry. This managerial team is a reflection of several changes that were made during fiscal 1996. The first change was the appointment of Ms. Audrey Jones Childs as Assistant Director for Administration and Operations. The second change was the consolidation of three associate directors into a single Associate Director, Professor Gregory N. Stephanopoulos. The Associate Director oversees the industrial collaborations, technology transfer, and the industrial consortia. A third change in management during fiscal 1996 is the addition of an Industrial Coordinator, Dr. James Leung. Dr. Leung has joined BPEC as a Consultant to coordinate the industrial activities. In addition to these changes, three new faculty members joined the center. These new members are Professor Hermann Steller, Departments of Brain and Cognitive Sciences and the Department of Biology, Professor Martin L. Yarmush, Mass General Hospital, and the Harvard-MIT Health Science and Technology Program, and Daniel Blankschtein, Professor of Chemical Engineering. Dr. Daniel I. C. Wang, Director of the BPEC, was honored with the position of Institute Professor on July 1, 1995.


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 of the center's activities.

A team of 14 faculty members participated in the center's activities from July 1, 1995 through June 30, 1996. They are from the Departments of Chemical Engineering (School of Engineering), Biology, Brain and Cognitive Science, and Chemistry (School of Science), the Mass. General Hospital/MIT's Harvard Science and Technology Program, Department of Chemistry at 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, 355 personnel took part in the center's research activities during fiscal 1996. This figure comprises of the following: 38 MIT Undergraduate Research Opportunities Program students (UROP), eight MIT Undergraduates working on course-related projects; 12 non MIT undergraduates from 12 different Universities who participated in the center's NSF Research Education for Undergraduates Program (REU); 102 graduate students from four departments; four technical assistants; 62 postdoctoral associates/fellows; 46 visiting scientists, engineers, industry researchers, five other administrative personnel and 14 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 were secured from outside sources. The center received industrial donations in the form 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, recruitment for the BPEC's outreach programs was lead by Ms. Araba Lamousé-Smith at the National Society of Black Engineering National Conference.


The goal of BPEC's educational programs is to train undergraduates, graduates, post-doctoral and industrial personnel. BPEC's vision in the educational programs is to incorporate biotechnology principles into our existing courses. This is being accomplished through course modifications and interdisciplinary teaching in the areas of chemistry, biology, and chemical engineering. The planning of our educational programs affects all sectors of the student body. To provide an industrial perspective to our students, course contents have been planned to incorporate real problems in biotechnology manufacturing. Invited lecturers from the biotechnology industry expose students to current day research problems.

To meet the goals and objectives of our educational visions, the course curricula for undergraduates, graduates and industrial personnel have continually undergone changes and implemented new initiatives. For example , to integrate biotechnology concepts as well as our research thrusts, several undergraduate courses have met the above challenges. These include "Chemical Kinetics and Reactor Design"; "Biotechnology and Bioengineering"; "Molecular and Engineering Aspects of Biotechnology"; "Chemical Engineering Project Laboratory"; and "Integrated Chemical Engineering." At the graduate level in education, a large number of courses have been modified to incorporate the research thrusts from the BPEC. In addition, new courses have been implemented as a direct result of the presence of the BPEC. The following courses taught by the BPEC faculty, relate directly to the BPEC's research thrusts: "The Folding Problem"; "Principles and Methodologies of Metabolic Engineering"; "Biochemical Engineering"; "Separation Process for Biochemical Products." Several graduate activities and courses that provide both cross-disciplinary principles as well as systems view were also taught by the BPEC faculty. Examples of these course activities are: "Cell Culture Optimization Consortium"; "Macromolecular Structure and Function Seminar"; and "Seminar on Pharmaceutical and Biotechnology Industry Management." To ensure the educational needs of industry are met, the BPEC provided one-week special summer courses. These courses included "Fermentation Technology", "Downstream Processing", "Advances in Controlled Release Technology and Delivery of Pharmaceuticals and Other Agents", and "Management for Physicians, Scientists, and Engineering in the Pharmaceutical and Biotechnology Industry."

The most recent educational initiative is the establishment of the "Metabolic Engineering Laboratory." This laboratory course is in its organizational stage that started in fiscal 1996 is to be tested in fiscal 1997. The National Science Foundation awarded additional administrative funding for the organization of this course.

One of the BPEC's goals is to ensure that the undergraduate students are integrated into the Center's research thrusts. The BPEC provides the initial research experiences to the undergraduates and encourages the students to work in industry as internees. For example, BPEC's industrial coordinators contacted 15 companies associated with BPEC for summer undergraduate internships. A total of 33 BPEC undergraduates was provided to these companies.

The two main BPEC outreach undergraduate programs are the Undergraduate Research Opportunities Program (UROP) and the Research Experience for Undergraduates (REU). The NSF funded REU program supported 12 non-MIT students. It is of interest to note that three REU students applied for graduate studies at MIT. Each student was required to present their research experiences during the center's summer seminar series "UROP and REU Seminar." The students were taught basic research and presentation tools during a "How to Give a Presentation" workshop series. As part of the student's research training, the BPEC instilled cross-disciplinary and team research in each student. All BPEC students were also invited to participate in the center's seminar series on Scientific Integrity that was lead by academic and industrial speakers.

Outreach activities in fiscal 1996 included participation of faculty from other universities along with their students in the center's research. Outreach activities by the BPEC included tours (i.e., a tour for 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 1996 summer months.

At the graduate level, the center continued to bring interdisciplinary ideas into the course teachings. BPEC successfully completed the seventh 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 chair. The BPEC graduated 24 Ph.D. candidates, four M.S. candidates, and seven B.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.

To ensure the educational needs of industry are met, the center has provided one-week special summer courses achieved through the Special Summer Course Program at MIT. In fiscal 1996, four special summer courses under the auspices of the BPEC were presented.


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. However within each thrust new concepts have been added due to the completion of some of the previous goals. BPEC presently has two main thrusts in research education and industrial involvement: Thrust I. Therapeutic Protein Production: Quantity and Quality; and Thrust II. Therapeutic Protein Aggregation, Stability, Formulation and Delivery.

In Thrust I, the increases in the quantity of therapeutic protein production are achieved by addressing nutrition, physiology, and biochemistry of cell metabolism in bioreactors. To improve the protein quality, modern and advanced bioanalytical characterization of glycoproteins in real-time is part of the overall goal. In particular, the BPEC is focused on the underlying reasons for macroheterogeneity (site occupancy) and microheterogeneity (antennary structure). In Thrust Area I, the two sub-thrusts deal with an integrated and systems view of quantity and quality in protein production. A major interface between these sub-thrusts as well as to Thrust Area II involves analytical monitoring and characterization of therapeutic proteins. The research foci contain both knowledge -based and technology-based concepts. For example, medium design and bioreactor control research is driven by principles in biochemistry and metabolism. We have demonstrated proof-of-concept and have improved significant the quantity of protein during production. This milestone allows us to explore technology transfer with industrial partners as a testbed for our achievements. A user-friendly algorithm from this research has been developed to enlarge our circle of testbed sites with multiple industrial partners. During the past year, two concepts were added to address the underlying reasons for cell death. The ultimate goal of this research sub-thrust is to provide the industry with rational and sound process development methodologies and the ability to produce therapeutic proteins with high productivity and in large quantity.

In Thrust II, the objective is to address protein aggregation, stability, formulation and delivery. This is the critical cost factor for therapeutic proteins since this final stage of production is associated with the highest cost. Protein aggregation is important in product stability, protein folding/refolding, disease state (amyloids) and vaccine virulency. During the past year knowledge-based milestones were achieved which included development of a novel technique to detect protein aggregation in its undenatured state, and demonstration that protein aggregation has specific pathways with multimeric polymerization as the mechanism. These findings are important in several future technological milestones which are the directions for our future programs.

The second sub-thrust focuses on the structure of solid protein formulations and the effects of bioprocessing parameters on protein stability. Our knowledge-based milestone has been demonstrated using FTIR spectra to monitor changes in the (-helical structures of solid proteins during lyophilization. This mechanistic understanding of structure-function relationships allows us to examine possible methods to stabilize proteins through the rational incorporation of excipients. A technology-based milestone has also been achieved, which addresses the lyophilization process parameters that affect protein stability. In addition, the pH history of a protein prior to lyophilization has also been demonstrated to effect protein stability. This finding is an important technological contribution toward protein stabilization. These milestones in protein stability have already been transferred to various industrial collaborators.

It has always been our strategy to affect our Center activities with interdisciplinary and multidisciplinary participants. Furthermore, an integrated approach in research and education is believed to be a major strength of our Center.


The industrial interactions during fiscal 1996 were achieved through both knowledge-based and technology-based advances. Industrial collaborations and technology transfer are important goals of the center. The BPEC's Industrial Advisory Board helps the center reach its goals. The Board consists of members from important sectors of industry and academia. Their function is to assess and plan both long-range and generic issues in research education. The board members are also in a position to forecast the future exciting developments in biotechnology. In addition to this Board, the center's Research Managers have shorter range goals and objectives with specific issues and defined technological barriers within their organization. One of their objectives is to serve as a conduit in identifying specific individuals or groups within a company for the detailed collaboration. As champions for the interactions, these Research Managers serve the important function to secure the necessary financial support for the collaborations.

Since there has been a gradual decline in the BPEC Consortium (38 current members), a new "Cell Culture Process Optimization Consortium" was planned and implemented between January 1995 to June 1995. The consortium was inaugurated in June 1995. The Director of this consortium is Professor Gregory N. Stephanopoulos. Eight BPEC faculty members are part of the consortium. There are presently four affiliate members and 10 companies who are in the process of becoming affiliate members. The BPEC interface with the consortium members is achieved through the consortium coordinator, Dr. James Leung.

Responsibilities of the BPEC's Industrial Consortium Office 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

In addition to this research consortium, the BPEC also collaborates with industry through other means. There are often very specific collaborations between a given BPEC faculty and a given company. Formal collaborations through these efforts are achieved via grants and contracts directly to the participating faculty. A total of 30 companies collaborates with the BPEC in its two research thrust areas. It should be noted that some companies collaborate on more than one project.

A further indication of the significance of the BPEC to industry is the large number of US companies that have visited the Center. Sixty visits were made this past year and represent the interests of the biotechnology industry to find out the cutting-edge research that we believe is important to the industrial sectors today and tomorrow.

There are several ways in which advances in technology can be reported. The knowledge-based information research represents one facet of technology transfer. This type of information transfer is presented by publications, presentations, and seminars. Our faculty presented 34 industrial seminars reaching an attendance of 1,875. In addition, the faculty made 125 technology-based presentations to societies, conferences, and symposiums; presented 42 seminars for academia; and published 192 BPEC thrust related publications.

Another example of significant advances in technology transfer is based on patents arising from the research in the Center. Patents represent novel and new concepts and can be considered to be an effective means for transfer technology. Twenty-three patents were filed by the BPEC faculty; five of these patents were granted; and nine patents were licensed during fiscal 1996.

Daniel I. C. Wang

MIT Reports to the President 1995-96