Great impact of Professor Daniel I.C. Wang and BPEC on development of biochemical engineering

doi:10.12211/2096-8280.2020-095

Abstract

Abstract:

Professor Daniel I.C. Wang was the founder of the Biotechnology Process Engineering Center (BPEC) at Massachusetts Institute of Technology (MIT). Under his leadership, BPEC has made remarkable achievements. It is a historical monument with great influence on the development of biochemical engineering. The historical background, outstanding contributions, innovative mechanisms, and significant impact of BPEC, led by Prof. Wang, were reviewed in this paper. (1) Leading biochemical engineering into a new era of biopharmaceuticals. With the development of genetic engineering in the 1970-1980s, a new era of modern biopharmaceuticals emerged. Professor Wang acutely felt that the production of biomacromolecule medicines by genetic engineering must solve a series of engineering science problems, which was the opportunity and challenge of biochemical engineering. He proposed to the National Science Foundation of the United States (NSF) for establishing BPEC at MIT. It was approved by the NSF in 1985. Compared with the initial concept of biochemical engineering at that time, the focus of BPEC had a great shift. The target molecules were no longer limited to microbial fermentation or bioconversion of antibiotics, chemicals and fuels. The mission of BPEC was to solve the engineering problems encountered by the large-scale production of various protein pharmaceuticals. In doing so, BPEC has successfully led biochemical engineering into the new era of biopharmaceuticals and established a unique position in the development of modern biotechnology. (2) Launching animal cell culture engineering. Animal cell culture is required for production of very complex biomacromolecules. While cell biologists were busy to scale up production by increasing the number of roller bottles, BPEC started engineering approach by design of bioreactors and control strategies. Successful bioreactor cultivation of mammalian cells was realized by minimization of shear stress and diffusion limitation. The culture nutritional composition was optimized by stoichiometric calculation. The strategy of nutritional medium addition was set up by metabolism analysis. Through intelligent cell culture control strategy and optimized reactor configuration, post-translational modification of the target protein was controlled at the optimal level to effectively avoid the loss of target protein. (3) Innovating separation and purification techniques for high quality biomacromolecules. Prof. Wang is one of the pioneers of biochemical separation engineering. He proposed biochemical separation engineering as another main direction of BPEC. Novel approaches such as affinity membrane, reversed micelles, electric-assisted separation were set up. He and his students discovered the mechanisms of protein refolding and aggregation. Using quasi-elastic light scattering technique, they were able to invent a novel technique of stabilizing refolding intermediates with polyethylene glycol. The smart work was published in Nature Biotechnology, and initiated various approaches of protein stabilization by different research groups. (4) Establishing a collaborative innovation and education system for biochemical engineering talents. Prof. Wang actively promoted the spirit of collaborative innovation, encouraged close collaborations among BPEC members, worked closely with biotechnology enterprises, and held lectures on downstream processing courses for R & D personnel of biotechnology companies in the US and other parts of the world. BPEC also attracted many young talents worldwide. Prof. Wang made the academic atmosphere of BPEC extremely active. The scientific exchange brought about brain storming to solve scientific and engineering problems. Numerous graduates and visiting scholars from BPEC have become successful professionals and entrepreneurs. (5) The influence of Prof. Wang and BPEC on biochemical engineering development in China. The influence of Prof. Wang and BPEC on biochemical engineering in China is the spirit of innovation. This spirit has been embodied to the strategic planning of the key laboratories and research directions from bioreactor to biocatalysis, from biological separation/purification to bioformulation, from equipment, media, and technologies to intelligent scale up productions. Biochemical engineering has become the support for sustainable development of life science and biotechnology in this country. Not only that, biochemical engineering researchers have integrated themselves into synthetic biology, gene editing, vaccine development and other frontier life science research, playing increasingly important roles.

Key words: biochemical engineering, biopharmaceuticals, bioreactors, bioseparation, bioformulation

摘要：

王义翘先生是美国麻省理工学院生物技术过程工程中心（BPEC）的创始人。在他的领导下，BPEC通过协同创新和生物化学工程（生化工程）的前沿探索，取得了显著的成就。（1）引领了生化工程进入生物制药新时代。与最初的生化工程概念相比，BPEC的重点发生了很大的转变，目标分子不再局限于抗生素、化学品和燃料等小分子，而是拓展到抗体、细胞因子、血液蛋白质和疫苗抗原等生物大分子，解决这些生物药品大规模生产所遇到的工程科学问题。（2）开启了动物细胞培养工程。当细胞生物学家忙于通过增加滚瓶的数量来扩大生产时，BPEC通过流体力学和传质分析，最大限度地减少剪切应力和扩散限制，成功地实现了动物细胞的生物反应器培养，设计出大规模培养的最佳培养基组成和添加策略，获得了蛋白质翻译后修饰随时间变化的规律，提高了动物细胞反应器的目标蛋白质产量。（3）创新了高质量生物大分子的分离纯化技术，建立了亲和膜、反胶束、电辅助分离等新方法。利用准弹性光散射技术，研究了蛋白质的再折叠和聚集机制，发明了聚乙二醇稳定再折叠中间体的新技术。（4）建立了生化工程协同创新和人才培养体系，促进了BPEC成员之间密切合作和与生物技术企业的密切合作，吸引和培养了众多在生化工程领域有建树的年轻人才。本文还对王义翘先生和BPEC对我国生化工程发展的启示和借鉴做了简要的评述。

关键词: 生化工程, 生物制药, 生物反应器, 生化分离工程, 生化制剂工程

CLC Number:

Q819

SU Zhiguo. Great impact of Professor Daniel I.C. Wang and BPEC on development of biochemical engineering[J]. Synthetic Biology Journal, 2021, 2(4): 470-481.

苏志国. 王义翘先生和BPEC对生物化学工程发展的巨大作用[J]. 合成生物学, 2021, 2(4): 470-481.

Figures/Tables 7

Tab. 1 Representative research on large-scale culture of animal cells under guidance of Prof. Wang

Prof. Wang’s student	Year of graduation / publication	Research project or topic	Reference
Hu W. S.	1986	Use of surface impeller to improve oxygen transfer in cell culture	[3]
Chiou T. W.	1990	A fiber‐bed bioreactor for anchorage‐dependent animal cell cultures	[4]
Xie L. Z.	1997	Stoichiometric medium design and nutritional control in fed-batch cultivation of animal cells	[5-6]
Nyberg G.	1998	Glycosylation site occupancy heterogeneity in Chinese hamster ovary cell culture	[7]

Fig. 1 Fiber bed bioreactor for animal cell culture that was designed by Prof. Daniel Wang and his students

Fig. 2 Process mechanism of protein refolding: formation of intermediates and possibility of misfolding and aggregation

Fig. 3 Process design of protein refolding in a reversed micelle

Fig. 4 Principle and operation of affinity membrane for adsorption separation of proteins

Fig. 5 Flux decline of cell-free protein solution through a microporous membrane

Fig. 6 Structure of research directions for State Key Laboratory of Biochemical Engineering

References 26

1	TRAFTON A. Longtime MIT professor launched the Biotechnology Process Engineering Center and influenced generations of students [EB/OL]. MIT News, 2020, September 2. .
2	HATTON T A. WANG D I C: A tribute to an inspirational leader and colleague [J]. Biotechnology and Bioengineering, 2006, 95(2): 262-269.
3	HU W S, MEIER J, WANG D I C. Use of surface aerator improve oxygen transfer in cell culture [J]. Biotechnology and Bioengineering, 1986, 28(1): 122-125.
4	MURAKAMI S, CHIOU T W, WANG D I C. A fiber‐bed bioreactor for anchorage‐dependent animal cell cultures (II): scaleup potential [J]. Biotechnology and Bioengineering, 1991, 37(8): 762-769.
5	XIE L Z. Stoichiometric medium design and nutritional control in fed-batch cultivation of animal cells [D]. MA, USA: Massachusetts Institute of Technology, 1997.
6	XIE L Z, WANG D I C. Fed-batch cultivation of animal cells using different medium design concepts and feeding strategies[J]. Biotechnology and Bioengineering, 2006, 95(2): 270-284.
7	NYBERG G. Glycosylation site occupancy heterogeneity in Chinese hamster ovary cell culture [D]. MA, USA: Massachusetts Institute of Technology, 1998.
8	YAO T, ASAYAMA Y. Animal-cell culture media: History, characteristics, and current issues [J]. Reproductive Biology and Endocrinology, 2017, 16: 99-117.
9	GASNER L L, WANG D I C. Microbial cell recovery enhancement through flocculation [J]. Biotechnology and Bioengineering, 1970, 12(6): 873-887.
10	CLELAND J. Mechanism of protein aggregation and refolding [D]. MA, USA: Massachusetts Institute of Technology, 1991.
11	CLELAND J L, BUILDER S E, SWARTZ J R, et al. Polyethylene glycol enhanced protein refolding [J]. Biotechnology, 1992, 10(9): 1013-1019.
12	HEBBI V, THAKUR G, RATHORE A S. Process analytical technology implementation for protein refolding: GCSF as a case study [J]. Biotechnology and Bioengineering, 2019, 116: 1039-1052.
13	YAMAMOTO E, YAMAGUCHI S, NAGAMUNE T. Protein refolding is improved by adding nonionic polyethylene glycol monooleyl ethers with various polyethylene glycol lengths [J]. Biotechnology Journal, 2017, 12(5): 1600689.
14	CHANG Y H D, GRODZINSKY A J, WANG D I C. Nutrient enrichment and in-situ waste removal through electrical means for hybridoma cultures [J]. Biotechnology and Bioengineering, 1995, 47(3): 319-326.
15	SPEED M A, KING J, WANG D I C. Polymerization mechanism of polypeptide chain aggregation [J]. Biotechnology and Bioengineering, 1997, 54(4): 333-343.
16	FOLLSTAD B D, BALCARCEL R R, STEPHANOPOULOS G, et al. Metabolic flux analysis of hybridoma continuous culture steady state multiplicity[J]. Biotechnology and Bioengineering, 1999, 63(6): 675-683.
17	HAGEN A J, HATTON T A, WANG D I C. Protein refolding in reversed micelles[J]. Biotechnology and Bioengineering, 1990, 35(10):955-965.
18	SU Z G, DAUN G, COLTON C K. Functionalized membranes for adsorption of proteins [C]// FURUSAKI S. Biochemical Engineering for 2001, Springer-Verlag Publishers, Tokyo, 1992: 533-538.
19	CHARCOSSET C, SU Z G, KAROOR S, et al. Protein A immunoaffinity hollow fiber membranes for immunoglobulin G purification: experimental characterization [J]. Biotechnology and Bioengineering, 1995, 48(4): 415-427.
20	KAROOR S, MOLINA J, BUCHMANN C R, et al. Immunoaffinity removal of xenoreactive antibodies using modified dialysis or microfiltration membranes[J]. Biotechnology and Bioengineering, 2003, 81(2): 134-148.
21	SU Z G, COLTON C K. Crossflow membrane filtration [M]// HARRISON R. protein purification process engineering (Chapter 4). New York: Macel Dekker, Inc., 1994.
22	SONG C F, LI Y G, WANG B C, et al. A novel anticoagulant affinity membrane for enhanced hemocompatibility and bilirubin removal [J]. Colloids and Surfaces B: Biointerfaces, 2021, 197: 111430.
23	AFEYAN N B, COONEY C L. Professor Daniel I.C. Wang: A legacy of education, innovation, publication, and leadership [J]. Biotechnology and Bioengineering, 2006, 95(2): 206-217.
24	CHANDAVARKAR A. Dynamics of fouling of microporous membranes by proteins [D]. MA, USA: Massachusetts Institute of Technology, 1990.
25	XIA Y F, WU J, WEI W, et al. Exploiting the pliability and lateral mobility of Pickering emulsion for enhanced vaccination [J]. Nature Materials, 2018, 17(2):187-194.
26	XIE X L, HU Y X, YE T, et al. Therapeutic vaccination against leukaemia via the sustained release of co-encapsulated anti-PD-1 and a leukaemia-associated antigen [J]. Nature Biomedical Engineering, 2021, 5(5): 414-428.

[1]	WU Shuke, ZHOU Yi, WANG Wen, ZHANG Wei, GAO Pengfei, LI Zhi. From single-enzyme catalysis to multienzyme cascade： inspired from Professor Daniel I.C. Wang’s pioneer work in enzyme technology [J]. Synthetic Biology Journal, 2021, 2(4): 543-558.
[2]	ZHANG Yi-Heng. Remembering Professor Daniel I.C. Wang’s contribution to biorefining and my perspective on the progress [J]. Synthetic Biology Journal, 2021, 2(4): 497-508.