MIT Reports to the President 1998-99

BIOTECHNOLOGY PROCESS ENGINEERING CENTER

The Biotechnology Process Engineering Center [BPEC] is a multi-disciplinary body with faculty members from the MIT Departments of Biology, Chemistry, and Chemical Engineering, the newly-established MIT Division of Bioengineering & Environmental Health [BEH], and the MIT-associated Whitehead Institute for Biomedical Research, along with the University of Toronto Department of Chemical Engineering. The mission of BPEC is to carry out research and education combining engineering with molecular biology, emphasizing a strong relationship with industry in its various activities. The goals of the Center are to perform cutting-edge, fundamental research in therapeutic gene and protein biotechnology based on contributions from, and interactions among, investigators from diverse relevant backgrounds.

Even while the mission of BPEC has remained unchanged, the central focus of BPEC's research directions has undergone a transition from the previous Therapeutic Protein Biotechnology [TPB] thrust to a new Therapeutic Gene Biotechnology [TGB] thrust. The TGB thrust is now being primarily fostered by the NSF ERC core funding, while support for the TPB thrust is being sought from a new industrial consortium. Major issues which are being addressed in the TGB thrust include problems associated with development of selective gene delivery vehicles for both ex vivo and in vivo approaches; the former emphasizes hematopoietic stem cells grown in culture and infected with viral vectors before implantation, whereas the latter emphasizes ligand-targeted synthetic or viral vectors with liver as a chief tissue objective.

The organization structure and management of BPEC has undergone major change over the past year. Douglas Lauffenburger has become Director, reporting to the Dean of Engineering (Professor Thomas Magnanti). The Director is also a member of Engineering Council, attending the pertinent weekly meetings which are related to BPEC participation in School of Engineering initiatives. Professor Harvey Lodish has become Associate Director for Research, Professor Linda Griffith Associate Director for Education, and Professor Daniel Wang Associate Director for Development. Daniel Darling is the Assistant Educational Coordinator, assisting the Associate Director for Education in all BPEC student activities. Darlene Ray is the Training Grant Coordinator, assisting the Director and Associate Director for Education in operation of the NIH Biotechnology Training Grant.

Dr. Peter Zandstra, an Assistant Professor at the University of Toronto Department of Chemical Engineering joined the Center faculty team during fiscal 99. In addition, Dr. Matthew Croughan has become Industrial Liaison. Dr. Croughan's duties include organizing the operations and activities of the Industrial Advisory Boards and Consortia, advising in technology transfer, and soliciting new industrial members.

A cross-disciplinary team consisting of biologists, chemists, and chemical engineers and bioengineers executes the research in two thrust areas: "Therapeutic Gene Biotechnology" and "Therapeutic Protein Biotechnology."

A team of 12 faculty members participated in the center's activities from July 1, 1998 through June 30, 1999. They are from the Departments of Chemical Engineering (School of Engineering), Biology and Chemistry (School of Science), The Whitehead Institute, and University of Toronto Department of Chemical Engineering. Undergraduate and graduate students, postdoctoral fellows, visiting scientists, and industrial associates are also integral participants in the center's activities.

Statistically reporting, 132 personnel took part in the center's research activities during fiscal 1997. This figure comprises of the following: 33 MIT Undergraduate Research Opportunities Program students (UROP), 12 non MIT undergraduates who participated in the center's NSF Research Education for Undergraduates Program (REU); 31 graduate students from four departments; 38 postdoctoral associates/fellows; 46 visiting scientists, engineers, industry researchers, four administrative personnel, five other director level personnel and 12 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 (35 percent), industry (23 percent), and other sources (42 percent) 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 (BTG), we formed a Faculty Steering Committee and a minority recruitment subcommittee. The NIH Faculty Training Grant Directors formed together to address not only recruitment activities, but other issues related to the Trainees.

A Responsible Conduct in Research and Academics session was held February 4, 1999. The purpose of this session is to offer tools for a better understands of laboratory ethics. Professor Stephanie Bird facilitated the session with audience and panel participation.

BPEC Headquarters are now located in Building 16, Room 429, with the Center core laboratories occupying the entire 4th floor of Building 16 with approximately 12,000 square feet of totally renovated and modernized laboratories.

The major biotechnology-related research in the Department of Chemical Engineering and the new Division of Bioengineering & Environmental Health are now all located contiguously in Buildings 16, 56, and 66. This consolidation and occupation of this totally renovated laboratory space represent over 60,000 square feet for biotechnology-related engineering research. This centralization and consolidation is clearly enhancing the interactions among the various BPEC investigators from Chemical Engineering and BEH.

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 million. However, the equipment in other BPEC investigator laboratories is now easily accessed. These include confocal microscope with video-imaging, ultracentrifuges, Coulter counters, fluorescence and phospor-imagers, bioreactors (2 liters to 52 liters) totally instrumented and computer-interfaced to name only a few items.

BPEC also has access to a wider array of equipment and facilities in support of its research, which is part of the Institute's programs. Some examples include scanning electron microscopy (Material Science and Engineering Center), fluorescence microscopy (Center for Biomedical Engineering), flow cytometry (Center for Cancer Research and Whitehead Institute), microfabrication (Microsystems Technology Laboratory), NMR spectroscopy (Magnet Laboratory and Department of Chemistry), and animal care (Division of Comparative Medicine).

Our objectives are to affect the education of undergraduate students, graduate students, and industrial personnel. A BPEC Student Council was formed during fiscal 1999 and consists of graduate, undergraduate, and postdoctoral students. The Council's primary focus is to help the Center meet its objectives.

At the undergraduate level, our goal is to ensure the students are integrated into our research thrusts for both MIT (UROP) students and students from other institutions (REU and high schools). To expose the students to cross-disciplinary activities and teamwork, the projects are selected carefully and critically.

Along with the ongoing important contributions of the Departments of Chemical Engineering, Biology, and Chemistry in providing aspects of educational programs relevant to BPEC's interdisciplinary biotechnology mission, significant complementary facets have been added in the past year deriving from the newly-established Division of Bioengineering & Environmental Health [BEH] in the School of Engineering. BEH continues to enhance its undergraduate curriculum aimed at integrating molecular cell biology with engineering: the Bio/medical Engineering [BME] BS Minor program. The BME Minor is MIT's first inter-Departmental minor degree, available to undergraduates taking any BS Major degree at the Institute. The goal of the degree program is to educate students in how to apply fundamental engineering principles to solve challenging problems in biology and medicine. A common theme is the integration of individual components of a biological system to describe both the spatial and temporal organization of the system as a whole. The scale of this integration may be as small as molecules and cells or as large as organ systems or whole organisms. Students gain an appreciation of how to solve problems at these different scales by taking two core biomedical engineering courses. They can then pursue particular interests through the two restricted electives in bio/medical Engineering.

An especially important facet of the BME Minor is an emphasis on inter-disciplinary research work combining engineering with biology. In addition to BPEC-sponsored UROP research, BEH offers a structured research subject (BEH.900: ‘Interdisciplinary Research in Bio/Medical Engineering'), in which the student must undertake the following formal requirements: (a) a brief research proposal emphasizing articulation of how engineering and biology will be combined in the project; (b) a mid-term written report and oral presentation, both critiqued by a faculty member other than the research supervisor; and, (c) a final written report and oral presentation, evaluated by that second faculty member. These requirements foster the student's independence and communication skills along with the research work itself.

We also supervise BS thesis research within BPEC; note that a BS thesis is not required at MIT. This provides further experiences for our undergraduates, preparing them for either industrial positions or further postgraduate studies. Within the undergraduate educational plan, the BPEC has modified existing courses to incorporate biotechnology concepts into the curriculum. New courses, especially related to the Center's research thrusts, are also in our overall plan. The goals of our undergraduate program are to provide to industry well-trained students at an annual rate of 30 students per year for industry, with 25 students per year entering graduate studies.

At the graduate level, one of the goals of BPEC is to provide research experience related to the Center's research thrusts. We ensure that the research is conducted with a spirit of teamwork and inter-disciplinary input. This is achieved by joint faculty advisors on the doctoral thesis and/or thesis committee members from different departments and disciplines. To provide industrial perspectives on the students' training program, industrial personnel are often members of doctoral thesis committees. In addition, our industrial collaborators have also participated in course lectures, both for undergraduates and graduates. To further integrate our graduate students into the industrial environment, our students are part of our technology transfer activities to industry. In this capacity, the students obtain valuable perspectives on industrial research and development and, at the same time, act as the conduit to testbeds at industrial sites. Our graduate students also actively participate as teaching assistants (TAs) in the courses which are related to the Center's research thrusts. This training provides experience in teaching in case the students are planning careers in academia.

Again, building upon the foundation of biotechnology-related graduate education continuing to be provided by the Departments of Chemical Engineering, Biology, and Chemistry, a major new development is the creation of a new PhD program in Bioengineering [BE] within BEH, beginning in Fall 1999. The central premise of BEH is that the science of biology will be as important to technology and society in the next century as physics and chemistry have been in the one now ending. Therefore, engineers and scientists must be educated who: (a) can apply their measurement and modeling perspectives to understanding how biological systems operate, especially when perturbed by genetic, chemical, mechanical, or materials interventions, or subjected to pathogens or toxins; and (b) can apply their design perspective to creating innovative biology-based technologies in medical diagnostic, therapeutic, and device industries, or in non-health-related industrial sectors such as agriculture, environment, materials, or manufacturing. Thus, the new BE PhD program in BEH aims to train graduate students to solve problems using modern biotechnology, emphasizing an ability to measure, model, and rationally manipulate biological systems. Accordingly, the curriculum will emphasize fundamental concepts more than particular applications. By learning to advance both engineering and biological knowledge, it is anticipated that the BPEC graduates from the Bioengineering PhD program will be well positioned to contribute to many areas of research in both academic and industrial settings–alongside BPEC graduates of the Chemical Engineering, Biology, and Chemistry doctoral programs.

The impact of the Center's educational achievements has been quite significant at MIT. Through the efforts of the BPEC, the Interdepartmental Biotechnology Training Program successful completed its 10th year. Twenty-two Training Faculty participate from the Departments of Biology, Chemistry, Chemical Engineering, and Mathematics, and the Division of Bioengineering and Environmental Health. This training grant is funded by NIH (NIGMS) with a total of 20 pre-doctoral trainees and recently received a new award for an additional five years.

To ensure the educational needs of industry are met, the Center has provided one-week special summer courses in fiscal 1999 which include "Fermentation Technology", "Downstream Processing", and "Advances in Controlled Release Technology and Delivery of Pharmaceuticals and Other Agents." These industrial courses typically have 50 to 75 attendees.

During the fiscal 1999 the Center graduated 6 PhD and 3 BS students. From this total, five graduates joined the industrial ranks.

During this past year of operation, BPEC has dramatically shifted 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 fundamentals-oriented, multi-disciplinary approach proven in its earlier incarnation. Investigator turnover of more than 50 percent along with changes in Director, Associate Directors, and Industrial Liaison have exemplified this substantial change in technical direction while retaining the same emphasis on solving fundamental problems of generic importance to the growth of nascent industries at the interface of engineering with molecular biology.

It is widely recognized that the crucial bottleneck holding back gene therapy from reliable implementation lies predominantly in the area of delivery 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) selectivity of transgene delivery and/or expression; (2) longevity of transgene expression or repeatability of transgene delivery; (3) efficiency of transgene delivery and 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 viral vectors, as a selective 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 ligand-targeted synthetic or viral vectors as selective in vivo gene delivery vehicles that can potentially offer repeatable retransfection. A critical problem for this approach is transfecting cells with adequate efficiency. As primary aims we are currently focusing on hematopoietic stem cell gene therapy via retroviral vehicles as an ex vivo application and on liver gene therapy via targeted synthetic polymer vehicles as an in vivo application.

Hence, we are vigorously underway with our new Therapeutic Gene Biotechnology thrust, comprising Stem Cell Delivery Vehicle and Targeted Delivery Vehicle subthrusts, nucleated by the NSF ERC core funding. At the same time, we are seeking to maintain our still-vital Therapeutic Protein Biotechnology thrust as a unique source of multi-disciplinary innovation in this application area, but moving into the future as a "self-sufficient" thrust supported by industrial funding.

To carry out the programs in this new Therapeutic Gene Biotechnology [TGB] thrust, five new investigators were recruited last year: George Daley (Medicine, Harvard Medical School; Fellow, Whitehead Institute), Linda Griffith (Chemical Engineering/Bioengineering & Environmental Health), Rudolf Jaenisch (Biology; Whitehead Institute), Douglas Lauffenburger (Chemical Engineering/Bioengineering & Environmental Health), and Peter Zandstra (Chemical Engineering, University of Toronto). At least one, and likely two, more are being added for the coming year: Shuguang Zhang (Biology/Center for Biomedical Engineering) and an individual currently being recruited. These now comprise the lead investigators in the TGB thrust along with three Co-PIs who had been previously participating in BPEC programs in the Therapeutic Protein Biotechnology [TPB] thrusts: Robert Langer (Chemical Engineering/Bioengineering & Environmental Health), Harvey Lodish (Biology/Bioengineering & Environmental Health; Whitehead Institute), and Philip Sharp (Biology). Thus, there has been well over 50 percent turnover of the BPEC investigators as we have made this major shift in direction. Lauffenburger became the new Director of BPEC in Summer 1998, with Lodish serving as Associate Director for Research and Griffith serving as Associate Director for Education along with Wang as Associate Director for Development. Furthermore, Dr. Matthew Croughan, a BPEC alumnus and former Senior Scientist in cell culture technology at Genentech, has joined us in the important position of Industrial Liaison; we also would like to add an MIT staff member as Assistant Industrial Liaison, focusing on student and facilities interactions with industry.

The two previous thrusts in Therapeutic Protein Biotechnology, which involve protein production in mammalian cell bioreactors and protein delivery, respectively, are undergoing a transition of support from NSF funding to industrial funding. Under the leadership of Matt Croughan, we are working with our TPB Industrial Advisory Board to create a framework for a new Industrial Consortium for this area.

At the January meeting of the CCO Board, we took the opportunity to not only collect information from the Board members on the strengths and weaknesses of the CCO Consortium, but also to engage them in planning toward an improved consortium in the future. This was particularly opportune, as many of the Board members are now uniquely experienced in high-level university-industry interaction. Many are also deeply committed to a partnership relationship with BPEC in therapeutic protein biotechnology and, in some cases, in therapeutic gene biotechnology also.

Agreed upon, in principle, at the January meeting was a proposition that would provide for the three major objectives of BPEC/industry interactions in the protein biotechnology field. These objectives are: (a) stimulation of leading-edge research aimed at generating advances in the knowledge-base and technology-base for solving fundamental problems in this field; (b) transfer of these advances into industrial context via awareness by our industrial partners of our activities; and, (c) transfer of these advances into industrial context via introduction of our students and associates to our industrial partners. The model we are proposing to follow, in order to achieve these objectives is based on what has worked successfully in the MIT Center for Biomedical Engineering, which Doug Lauffenburger directed during the period 1995—1998.

In line with these principles, a detailed plan for a new high-level consortium in therapeutic protein biotechnology was written. It incorporates concepts and strategies presented in earlier sections of this report, along with ideas discussed at the CCO Board at the January 1999 meeting and in subsequent informal discussions with Board members. A draft of this plan has been distributed to the CCO Board members for their review. We plan to collect their input up front, on points clearly stated in explicit detail. Subsequent commitment and buy-in should be straightforward.

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 involvement.

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 38 companies collaborated with the BPEC in its research Thrust Areas during fiscal 1999, with some of these companies collaborating on more than one project with the Center.

More information about this center can be found on the World Wide Web at http://web.mit.edu/bpec/.

Audrey Jones Childs, Douglas Lauffenburger

MIT Reports to the President 1998-99