MIT Reports to the President 1997-98
The Biotechnology Process Engineering Center (BPEC) is a multidisciplinary body with faculty members from Departments of Biology, Chemistry and Chemical Engineering as well as from the MIT Whitehead Institute. The BPEC was established in 1985 and is funded by the National Science Foundation (NSF) under the Engineering Research Center Initiative. The missions of the Center are to carry out multidisciplinary research and education with a strong relationship with industry in all of its activities. The goals of the Center are to perform cutting-edge, generic research in biotechnology with a strong component of interdisciplinary collaboration.
The organization structure and management of the Biotechnology Process Engineering Center (BPEC) is going through a major change. The present Director, Professor Daniel I.C. Wang, has planned to step-down as of September 1, 1998. The new Director will be Professor Douglas A. Lauffenburger. Professor Lauffenburger served as the Executive Director of the Center during fiscall 1997 in preparation for the new change.
The center Director reports directly to the Dean of Engineering (Professor Robert A. Brown). The Director is also a member of the Engineering council attending the pertinent weekly meetings, which are directly related to the Center's activities.
There are two Industrial Advisory Boards to assist the planning and assessment on the Center's activities. These two Boards are Industrial Advisory Board in Protein Production (11 members) and Industrial Advisory Board in Gene Therapy (10 members). Two new Associate Directors have been selected to oversee the research and education programs. The Associate Director for Research is Professor Harvey F. Lodish (Department of Biology and Whitehead Institute) and the Associate Director of Education is Professor Linda G. Griffith, and is assisted by the Educational Coordinator, Ms. Lorraine E. Cable. The Education Coordinator processes all of the UROP and REU affairs in the Center.
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. One full time and one part-time administrative staff workers in addition to the Education Coordinator assist Ms. Childs.
Three additional faculty members were added to the Center during fiscal 1997, Professors George Q. Daley, Linda G. Griffith, and Rudolph Jaenish. These additions are directly related to the Center's present activities as well as the future initiatives in nucleic acid biotechnology.
A cross-disciplinary team consisting of biologists, chemists, and chemical engineers executes the research in two thrust areas: 1. Therapeutic Gene Biotechnology, 2. Therapeutic Protein Production: Quantity and Quality, 3. Therapeutic Protein Aggregation, Stability, Formulation and Delivery.
A team of 14 faculty members participated in the center's activities from July 1, 1997 through June 30, 1998. They are from the Departments of Chemical Engineering (School of Engineering), Biology and Chemistry (School of Science), The Whitehead Institute, and the University of Maryland, Department of Chemistry. 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: 80 MIT Undergraduate Research Opportunities Program students (UROP), two MIT Undergraduates working on course-related thesis projects; 12 non MIT undergraduates from 10 different Universities who participated in the center's NSF Research Education for Undergraduates Program (REU); 77 graduate students from four departments; 48 postdoctoral associates/fellows; 22 visiting scientists, engineers, industry researchers, four other administrative personnel and 14 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.
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, Ms. Lorraine Cable solicited 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--1, Pacific Islander--1, African American--2, Hispanic--4.
Some major changes occurred during fiscal1998 with respect to the BPEC's headquarters and associated laboratories of the Center. As of March 12, 1998, the BPEC moved from Building 20A into its new space in Building 16. The Center's Headquarters are now located in Building 16, Room 429. The Center's laboratories occupy the entire fourth floor of Building 16 with approximately 12,000 square feet of totally renovated and modernized laboratories.
The major "bio-related" research in the department of Chemical Engineering are now all located contiguously with Building 66 (Department of Chemical Engineering). Five of the Chemical Engineering faculty members in the BPEC (C.L. Cooney, D.A. Lauffenburger, L.G. Griffith, G.N. Stephanopoulos and D.I.C. Wang) now occupy contiguous laboratory and office spaces on the 3rd and 4th floors of the adjoining buildings 16 and 56. This consolidation and occupation of this totally renovated laboratory space represent over 60,000 square feet for "bio-related" research. This centralization and consolidation will greatly increase the interactions among the various ERC researchers in the future as well as with other students in the Department.
Through this consolidation and proximity of the laboratories in Building 16 and 56, the equipment and facilities for researchers in the BPEC will also be vastly increased. Presently, the core equipment in the BPEC include major items such as MALDI/TOF Mass Spectrometer, Biocad and Integral Liquid Chromatography, other HPLCs, Scintillation Counter, Coulter Counter plus many other equipment valued in excess of $4,0 million. However, the equipment in other BPEC facility member's laboratories is now easily accessed. These include Confocal Microscope with Video-Imaging, Ultra Centrifuges, Coulter Counters, Fluorescence Imager, Bioreactors (2 liters to 52 liters) totally instrumented and computer interfaced to name only a few items.
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 had new initiatives implemented. For example, to integrate biotechnology concepts as well as our research thrusts, several undergraduate courses have been instituted. "Chemical Kinetics and Reactor Design": Biochemical reactions have been included in this undergraduate core course; "Biotechnology and Bioengineering" (Joint Chemical Engineering/Chemistry): Integrating principles in biology, chemistry and chemical engineering of therapeutic protein production. Directly related to the Center's research thrusts; "Molecular and Engineering Aspects of Biotechnology" (Joint Biology/Chemical Engineering): Integrating molecular biology and biochemical engineering principles in the production of therapeutic proteins from mammalian cells. Directly related to the Center's research thrusts. "Chemical Engineering Project Laboratory" (Chemical Engineering): Projects designed for undergraduates to examine protein quantity and quality from mammalian cells. Directly related to the Center's thrusts. "Integrated Chemical Engineering" (Chemical Engineering): Two modules with a systems view on biotechnology manufacturing as part of the undergraduate core curriculum. 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 Center. In addition, new courses have been implemented as a direct result of the presence of the Center. Graduate courses presented by the Center's faculty during fiscal 1998 are: "The Folding Problem" (Joint Biology, Chemical Engineering and Chemistry): Mechanism and pathways of protein aggregation and folding relating to the biotechnology industry. Directly related to the Center's thrusts; "Principles and Methodologies of Metabolic Engineering" (joint Biology and Chemical Engineering): Application of chemical engineering principles and genetic techniques to the analysis and modification of metabolic pathways of bacteria and mammalian cells. Directly related to the Center's thrusts; "Biochemical Engineering" (Chemical Engineering): Integration of chemical engineering, biochemistry and microbiology in biochemical processes. Directly related to the Center's thrusts; "Separation Processes for Biochemical Products" (Chemical Engineering): Fundamental principles of separation operations for the recovery of biological products. Directly related to the Center's thrusts; "Tissue Engineering" (Chemical Engineering): A new course dealing with cell growth on artificial matrices. Principles in course include metabolism, regulation transport phenomena. This course is directly related to the new research thrust in Gene Therapy; "Cell Bioengineering" (Chemical Engineering): A new course in the analysis of mammalian cell function from quantitative and engineering perspectives; directly related to Center's research thrusts.
There are several graduate courses that provide both cross-disciplinary principles as well as systems view which were in the fiscal 1998 curriculum. The highlights of these courses are "Macromolecular Structure and Function Seminar": As the direct result of the research in Thrust Area II (Protein Aggregation and Folding), this seminar represents an institutional forum to discuss research of mutual interests. Participants have been from a wide variety of disciplines including Biology, Brain and Cognitive Science, Chemistry and Chemical Engineering; "Seminar on Pharmaceutical and Biotechnology Industry Management": A joint seminar (Biology, Chemical Engineering and Sloan School) dealing with management, finance, regulatory, R&D and manufacturing in the biotechnology industry.
To ensure the educational needs of industry are met, the Center has provided one-week special summer courses in fiscal 1998 which include "Fermentation Technology", "Downstream Processing", "Advances in Controlled Release Technology and Delivery of Pharmaceuticals and Other Agents", "Management for Physicians, Scientists, and Engineering in the Pharmaceutical and Biotechnology Industry", "Methods, Logic and Opportunities in Metabolic Engineering": This is a new summer continuing education course to be offered in August 1997. This course is a direct result of the research thrust of the ERC.
These industrial courses typically have 50 to 75 attendees, which represent the training of 250 to 300 industrial participants annually.
The impact of the Center's educational achievements has been quite significant at MIT. Through the efforts of the BPEC, an Interdepartmental Biotechnology Training Program was established. This training grant has faculty participants from five (5) MIT departments: Biology, Chemistry, Electrical Engineering and Computer Science, Chemical Engineering and Math, with a total of 25 faculty mentors. This training grant is funded by NIH (NIGMS) with a total of 20 pre-doctoral trainees.
The demonstration of cross-disciplinary training by the BPEC has encouraged other MIT programs to emulate our success. Our model was used to formulate an interdisciplinary Human Genome Science Training Grant with faculty participants from Biology, Chemistry, Chemical Engineering, Electrical Engineering and Lincoln Laboratory. This grant was funded through the NIH; six pre-doctoral and 3 post-doctoral traineeships were awarded. Here again, the focus of this research-training grant is on cross-disciplinary interactions among the different departments at the Institute.
A last example of the institutional impact of the BPEC is the following new initiative by the Department of Chemical Engineering. In order to provide the School of Engineering's faculty with an awareness of the role of molecular biology in future engineering research, a special one-week intensive course on molecular biology was held in June 1996. A total of 25 engineering faculty members participated in this course along with two biology lecturers from the BPEC. This molecular biology course was extremely well received in 1996 by the engineering faculty and was repeated in 1997 with participation by 25 engineering faculty members. The significance of this is the direct result of the BPEC and its various activities in biotechnology, which, in the future, will have an impact on all departments in the School of Engineering.
The most important product from the BPEC in all its years at MIT has been the outstanding body of students it has produced who have joined industry, university and government. At a time when major industries have faced employment reduction and cutbacks, we have not found this to be true with respect to BPEC graduates. Following are several examples that illustrate the impact of our educational and training achievements. The BPEC's Undergraduate Research Opportunity Program (UROP) has provided a superb foundation for our undergraduates. Upon graduation, these students are singled out for industrial summer internships as well as exciting careers in industry. An example of our educational impact is the breadth and depth of the training the Center has provided to our graduates. Small start-up biotech companies (e.g., Advanced Tissue Sciences, Khepri, Tanox Biosystems, etc.) have sought out our graduates due to the diversity of their training experiences.
As a second example of the training of students with a systems view in manufacturing is the recently founded company Covance, Inc. This is a contract manufacturing and development services company for therapeutic proteins with a GMP facility in Research Triangle Park, NC. The Vice President and Chief Scientific Officer of Covance is a graduate of out program and two senior bioprocess engineers were graduates and participants in the BPEC.
On the other hand, large pharmaceutical companies (e.g., Merck & Co.) have hired a large number of our graduates. The reasons Merck gave us for seeking out our graduates were:
During the fiscal 1998 the Center graduated 16 PhD, 2 MS and 2 BS students. From this total, 60% joined the industrial ranks and 40% went to academia either as faculty members or to graduate school to continue their education.
We believe we have fulfilled the visions and goals of our educational programs and will continue to excel in the future.
RESEARCH HIGHLIGHTS AND FUTURE PLANS
The Center continued to focus on its two main research thrusts during fiscal 1998. Thrust 1: Therapeutic Protein Production: Quantity and Quality was lead by Professor Gregory N. Stephanopoulos and a team of five other faculty members ( Harvey F. Lodish, Philip A. Sharp, Charles L. Cooney, and Daniel I. C. Wang). Thrust 2: Therapeutic Protein Aggregation Stability, Formulation and Delivery was lead by Professor Jonathan A. King and Alex M. Klibanov and a team of four other faculty members (Charles L. Cooney, Cheng S. Lee - University of Maryland, Robert S. Langer, Daniel I. C. Wang). Research results from these thrusts are seen through the number of collaborative projects and industrial members mentioned in the Technology Transfer section below.
The Center is moving its primary direction from therapeutic protein biotechnology to therapeutic gene biotechnology, in order to attack bottleneck problems in this highly promising new area using the multi-disciplinary approach proven in its previous incarnation. Investigator turnover of more than 50% along with a change in Director characterize this substantial change in technical direction while retaining the same emphasis on solving fundamental problems of generic importance for aiding the growth of a nascent industry.
It is widely recognized that the crucial bottleneck holding back gene therapy from reliable implementation lies predominantly in the area of delivery, much more than in discovery and production, at the present time. In particular, effective delivery of a therapeutic transgene is typically limited by one or more of the following issues, depending on the approach and application: (1) longevity, or repeatability, of transgene expression; (2) selectivity of transgene expression; (3) efficiency of transgene expression; (4) regulation of transgene expression. Our new BPEC program is dedicated to creating new fundamental knowledge, enabling technology, and a systems perspective addressing these issues in focused manner, synergistically combining bio/chemical engineering with molecular cell biology.
Recognizing that different applications will require differing delivery vehicles, we are currently focusing our research efforts on two chief approach categories motivated by the issues listed above--representing ex vivo and in vivo approaches, respectively. One approach category is the use of pluripotent stem cells transfected via chromosomal-integrating retroviral vectors, as an ex vivo gene delivery vehicle that can potentially offer expression longevity. Critical problems for this approach are expanding these cells to significant numbers in culture, and obtaining high transfection efficiencies for reimplantation. The second approach category is the use of nonviral targeted polyplexes as an in vivo gene delivery vehicle that can potentially offer expression selectivity and repeatable retransfection. A critical problem for this approach is transfecting cells with adequate efficiency. In both of these two approaches--ex vivo stem cell delivery and in vivo targeted polyplex delivery--a capability for regulating transgene expression at the tissue level using small molecule drugs. We are therefore pursuing research directed toward this capability in relation to both delivery approaches. As ultimate aims we are focusing on hematopoietic stem cell gene therapy via retroviral vehicles as an ex vivo target application and on liver gene therapy via molecular conjugate vehicles as an in vivo target application. Accordingly, a centerpiece of our efforts is the development of tissue-engineered "vascularized" hematopoietic and liver cell microarrays to serve as a unique model testbed integrating all research projects.
INDUSTRIAL COLLABORATIONS AND TECHNOLOGY TRANSFER
Industrial collaboration and technology transfer are accomplished through a number of different routes. In the BPEC, one of the major avenues leading to collaborations and technology transfer is through our Industrial Consortium. The "Cell Culture Process Optimization Consortium" was established in 1996. The Director of this Consortium is Professor Gregory N. Stephanopoulos. Since December 1997, this industrial consortium has integrated the research for both Thrust Areas I and II. (Thrust I: Therapeutic Protein Production and Thrust II: Protein Aggregation, Stabilization and Delivery.) There are presently 14 companies in this consortium. Each member contributes $25,000 annually. The benefits for the consortium members include: Participation in the planning of the Center's research; serving on doctoral thesis committees; semi-annual reports on the research progress; licensing rights to the research; access to the BPEC's facilities and personnel; direct technology transfer and testbeds at BPEC or company sites; and recruitment of BPEC students.
The interface between the consortium members and the BPEC is through the Industrial Coordinator, Dr. James C. Leung. Through the Coordinator, the semi-annual reports are gathered and transmitted to the industrial members. Dr. Leung is also responsible for organizing the consortium meetings. During fiscal 1998, five (5) consortium meetings have been held at the BPEC: February 1997, July 1997, November 1997, December 1997 and April 1998.
Collaboration and technology transfer initiations with consortium members are achieved mainly from the consortium meetings. At those meetings, the research results are presented and potential collaborations and technology transfers are then addressed. The follow-up for these activities by the Industrial Coordinator is then exercised.
There are also other ways to affect industrial collaborations and technology transfer outside of the Industrial Consortium. These involve visits by companies to the BPEC, research contracts with companies, and seminars or consulting by the BPEC faculty with companies. We have found these latter methods are equally effective for industrial involvements.
Industrial collaborations play many important roles in achieving the success of the BPEC's goals as presented in our strategic plan. First, when industrial participants are active and collaborative partners in research and development, the collaborations are guaranteed to be relevant to industrial activities. Second, without industrial collaborations, much of our research would be difficult if not impossible to implement. For example, easy access to reagents, recombinant cell lines, analytical methodologies, etc., reduces dramatically the time required to reach the goals of both the Center and industry. Third, expertise that resides in the companies and complements our technical compatibility plays a synergistic role in reaching our goals. Fourth, these collaborations provide realism to our students' and faculty's research. Fifth, although industry is in many instances more focused on its own immediate needs, it can still recognize the importance of fundamental and generic research by a Center which would aid their future programs. Sixth, industry provides an excellent testbed for deliverables in assessing both knowledge-based and technology-based research and development. Seventh, when mutual satisfaction is achieved in successful collaboration, industrial representatives can act as an excellent spokespeople on the Center's behalf. Lastly, the financial support, equipment and materials donations from industrial sources represent significant leverage for the Center's financial base. A total of thirty-two companies are members of the Center.
A total of 41 companies collaborated with the BPEC in its research Thrust Areas during fiscal 1998, with some of these companies collaborating on more than one project with the Center.
Twenty-six different items ranging from enabling technologies to new reagents have been transferred in 1997-1998. One important item to be mentioned is the association with Concordance Biosystems, Inc. This is a spin-off company using patents and research findings in our Thrust Area III.
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 1997-98