The Biotechnology Process Engineering Center (BPEC), an interdepartmental center at the Massachusetts Institute of Technology, established in May 1985, is funded by the National Science Foundation (NSF) under the Engineering Research Center Initiative. Through the BPEC's multidisciplinary body of faculty members, the center executes its educational, research and industrial functions to ensure the competitiveness of the US biotechnology industry. The vision and goals of this Center is to act as pioneers and leaders to the academic, industrial and government communities; to perform cutting-edge and generic research; to foster interdisciplinary educational activities; and to initiate relationships with industry, involving both collaboration and technology transfer.
INFRASTRUCTURE
As an interdepartmental center, the BPEC reports to the Dean of Engineering, Robert A. Brown. The two research thrust areas each have Thrust Area Leaders. In Thrust Area I: Therapeutic Protein and Nucleic Acid Production, the Thrust Area Leaders are Professor Gregory N. Stephanopoulos (Chemical Engineering), Professor Anthony J. Sinskey (Biology), and Professor Martin L. Yarmush (Mass General Hospital). The leaders in Thrust Area II: Protein and Nucleic Acid Aggregation, Stability, Formulation and Delivery, are Professor Alexander M. Klibanov (Chemistry) and Profess Jonathan A. King (Biology). The Thrust Areas meet once a month for half a day to discuss the research and future programs. An Industrial Advisory Board assists the center in its overall management. Since the Board members are also part of the center's Industrial Consortium, they attend the center's biannual consortium meetings. At these meetings, the Board members meet in a separate executive session with the center's Director and the Thrust Area Leaders. Input from the Board members is provided by the members both orally and in a written report submitted to the center's Director.
The BPEC faculty execute the strategic planning of the center's research and other activities. These meetings are generally divided into the two research thrusts with certain faculty members overlapping in both thrusts. During fiscal 1997, six strategic planning meetings were held in order to plan the center's long-range research activities. The Associate Director of the center is Professor Gregory N. Stephanopoulos. The major role played by the Associate Director is the planning and execution of the research, as well as acting as the primary faculty interface with the Industrial Consortium. To assist the Associate Director with the industrial programs is Dr. James C. Leung, the Industrial Coordinator.
Ms. Audrey Jones Childs is the Assistant Director for Administration and Operations. The Assistant Director handles the center's human resource, purchasing, prepares and monitors all budgets and proposals, and prepares statistical reports. In addition, the Assistant Director is the direct liaison with the School of Engineering. Both the Director and Assistant Director are liaisons with the National Science Foundation ERC Division. Three part-time administrative staff workers in addition to the Education Coordinator assist Ms. Childs. One additional faculty member was added to the center during fiscal 1997, Professor Douglas A. Lauffenburger. This addition was made due to Professor Lauffenburger's research interests which are directly related to the center's present activities as well as the future initiatives in nucleic acid biotechnology.
RESEARCH STRUCTURE
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 15 faculty members participated in the center's activities from July 1, 1996 through June 30, 1997. 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 also integral participants in the center's activities. Statistically reporting, 254 personnel took part in the center's research activities during fiscal 1997. This figure comprises of the following: 83 MIT Undergraduate Research Opportunities Program students (UROP), four MIT Undergraduates working on course-related thesis projects; 16 non MIT undergraduates from 14 different Universities who participated in the center's NSF Research Education for Undergraduates Program (REU); 63 graduate students from four departments; 51 postdoctoral associates/fellows; 33 visiting scientists, engineers, industry researchers, four other administrative personnel and 15 faculty.
The NSF provides the major financial support for BPEC personnel. The National Institutes of Health (NIH-NIGMS) provides additional support for graduate educational activities for the MIT students. The NSF (34%), industry (24%), and other sources (42%) support the center's research and administration.
AFFIRMATIVE ACTION
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 strengthen the number of applicants for the National Institutes of Health Interdepartmental Training Grant, we reformed our minority recruitment committee this past year to analyze and address the current recruitment procedures. Ms. Araba LamousÈ-Smith has been appointed chairperson of this committee. The following two specific examples highlight BPEC's recruitment activities. First, Ms. Araba LamousÈ-Smith again recruited undergraduates at the National Society of Black Engineering National Conference. Second, Mr. John Galvin researched contacts at additional minority universities, colleges and programs for the REU solicitation. Our recruiting effort was quite successful, having under-represented populations in the BPEC in the following numbers; American Indian--3, Pacific Islander--2, African American--5, Hispanic--3.
EDUCATIONAL ACTIVITIES
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" (Biochemical reactions have been included in this undergraduate core course; "Biotechnology and Bioengineering" (directly related with the center's thrusts); "Molecular and Engineering Aspects of Biotechnology" (directly related to the center's thrusts); "Chemical Engineering Project Laboratory" (directly related to the center's thrusts); "Integrated Chemical Engineering" (directly related to the center's thrusts); Interdisciplinary Research in Biomedical Engineering" (a new course integrating biology with 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. A summary on graduate courses presented 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"; "Tissue Engineering"; "Cell Bioengineering." The BPEC faculty also taught several graduate activities and courses that provide both cross-disciplinary principles as well as systems view. Two highlights of these courses are the "Macromolecular Structure and Function Seminar" and "Seminar on Pharmaceutical and Biotechnology Industry Management."
To ensure the educational needs of industry are met, the center provided one-week special summer courses this past year. 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"; and "Methods, Logic and Opportunities in Metabolic Engineering."
The most recent educational initiative of the center is the establishment of the "Metabolic Engineering Laboratory (MEL)" in 1995. Although still in its organizational stage that started in fiscal 1996, progress has been made towards establishing a MEL in the curriculum of the Chemical Engineering Department. The original target date of fiscal 1998 for testing the MEL is still anticipated. 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, one of BPEC's industrial coordinators contacted 49 companies associated with BPEC for summer undergraduate internships. Thirty-three contacts responded requesting rÈsumÈs for summer internships: 29 contacts responded requesting rÈsumÈs for permanent positions. The industrial respondents represented 19 companies/institutions.
The two main BPEC outreach undergraduate programs are the Undergraduate Research Opportunities Program (UROP) and the Research Experience for Undergraduates (REU). A total of 83 MIT UROP students participated in the center this past year. The NSF funded REU program supported 13 non-MIT students. Of this total, four of the REUs were supported by BPEC's unrestricted funds since we wish to assure our commitment toward under-represented minorities. The students were required to present their research experiences during the center's summer seminar series "UROP and REU Seminar." They 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 required to participate in the center's seminar series on Scientific Integrity that was lead by academic and industrial speakers.
Two BPEC faculty members presented lectures and conducted laboratory tours as part of MIT's High School Teachers Program in Science and Engineering. At these lectures, the goal is to excite the teachers with new developments in biotechnology. A teacher from the Hebron Academy School in Hebron, Main, after hearing the lecture, worked with BPEC to arrange a follow-up visit by 11 students to the BPEC. In addition, BPEC faculty participated in the Annual Lecture Series for High School Students held at MIT in February 1997. Previous graduates of the BPEC led panel discussions on the exciting future of biotechnology and nine biotechnology companies sponsored the lecture series. Five of these companies have been or are presently affiliated with the BPEC.
This center also has an outreach research program to other universities. Three of BPEC's faculty members are not from MIT; these other home institutions are Purdue University (F.E. Regnier), Iowa State University (C.S. Lee) and Massachusetts General Hospital (Martin L. Yarmush). Research programs at these different universities are integrated in the center's programs. In addition, students from these universities have spent time during fiscal 1997 summer months in BPEC labs; in addition, the center's students, too spent time at these other universities.
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 20 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.
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.
Our educational advances have had an impact on both undergraduate and graduate students through the cross-disciplinary courses that will broaden the students' knowledge base for entering industrial biotechnology sectors. Especially significant to undergraduates, our educational activities have penetrated their curriculum and enhanced their interest in future careers in biotechnology. The potential of this new breed of students represents a real benefit to industry. On the graduate level, the significance of our research thrusts have been incorporated into new courses which will expose these candidates to important needs required to solve problems facing the biotechnology industries, as well as their possible future careers in academia. It is our belief that students are our most valuable product and that our training programs have provided a cadre of leaders for tomorrow.
CURRENT RESEARCH
The vision of the BPEC is to promote the success of the US biological industry by being pioneers and leaders to the academic, industrial and government communities in the planning and implementation of research and education. This visionary approach is especially important in the field of biotechnology since scientific breakthroughs are constantly occurring breakthroughs which in turn affect the technological aspects of manufacturing. Our vision for the past 12 years has not changed insofar as we have continually predicted and reaffirmed the importance of therapeutic proteins for the biotechnology and biopharmaceutical industries. 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.
The research in Thrust I is organized into four subareas: 1. Method development: including laboratory analytical techniques, as well as inofmration analyses, such as Metabolic Flux Analysis, material and energy balances. 2. Glycosylation: including microheterogeneity, macroheterogeneity, and genetic modification of glycosylation processing. 3. Apoptosis: including environmental effects, manipulation of genetic controls and cell physiology. 4. Process Operations: including medium design/process control, and sparging/scale-up of bioreactors. One of the purposes for the creation of this thrust area is to provide an integrated approach and a systems view of the research. We have adopted a virtual toolbox concept for the research activities within the thrus area. These tools are available for the use of all researchers who need them for their work. In addition, the tools and methods we develop and publicize are available to the industrial members of the Consortium by request. The transfer of these methods and techniques offers opportunities for direct interactions between industry and the researchers.
The research in thrust area II addresses stability, formulation and delivery. Protein aggregation is important in product stability, protein folding/refolding, disease state (amyloids) and vaccine virulence. The second subthrust focuses on the structure of solid protein formulations and the effects of bioprocessing parameters on protein stability. The 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 in addressing the parameters that affect protein stability in lyophilization process. The milestones in protein stability have already been transferred to various industrial collaborators. The last areas of research focuses on delivery systems for macromolecules. The objective of our research is to devise new and novel means for the delivery of macromolecules such as therapeutic proteins.
INDUSTRIAL COLLABORATIONS AND TECHNOLOGY TRANSFER
The industrial interactions during fiscal 1997 were achieved through both knowledge-based and technology-based advances. Industrial collaborations and technology transfer are important goals of the center. In the past the BPEC's Industrial Advisory Board, met once a year. Therefore, in fiscal 1997, members of our research Consortium replaced the earlier Industrial Board. The reason for this replacement was the research Consortium's better knowledge of the center's activities. Thus we believe the Board as it now stands is able to provide better advice and planning to the center. 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. These managers serve as a very important function to the BPEC: they serve as champions of the BPEC in their collaborations with the company's upper management.
The center's Cell Culture Process Optimization Consortium was expanded during fiscal 1997 to include all the center's research. The Director of this consortium is Professor Gregory N. Stephanopoulos. All of the BPEC faculty members are part of the Consortium. There are presently 13 companies in this Consortium, each of which contribute $25,000 per year for two years. There are two annual meetings, each 1[Omega] days in duration. The benefits to the Consortium members include: participating in the planning of the center's research; serving on doctoral thesis committee of students; semi-annual reports on the center's research progress; licensing rights to research findings; access to BPEC facilities and personnel; direct technology transfer and testbeds at BPEC or company sites. 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 38 companies collaborate 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. These visits represent the interest the biotechnology industry exhibits in learning about the cutting-edge research that we believe is important to the industrial sector today and will be tomorrow. Fifty US companies visited the BPEC this past year.
A useful method of demonstrating the center's industrial collaboration is by presenting the actual transfer of technologies to companies by the center. Twenty-two companies were recipients of technologies transferred from the BPEC during fiscal 1997.
There are several ways in which advances in technology can be reported. The knowledge-based information research represents one facet of technology transfer. Publications, presentations, and seminars present this type of information transfer.
The center faculty presented 32 industrial seminars reaching an attendance of 1,751. In addition, the faculty made 97 technology-based presentations to societies, conferences, and symposiums; presented 67 seminars for academia; and published 178 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. The BPEC faculty filed eight patents during fiscal 1997; 22 of these patents were granted; and one was licensed.
More information about this center can be found on the World Wide Web at the following URL: http://web.mit.edu/bpec/
Daniel I. C. Wang
MIT Reports to the President 1996-97