Wei He

Research Scientist
Biosciences and Biotechnology Division
Email: he4@llnl.gov
Phone: +19254235121

Personal statement

I earned my B.S. in Microbiology from Fudan University and a Ph.D. in Pharmacology and Toxicology from University of California at Davis. I have over 18 years’ experience in molecular biology and biochemistry. My graduate work focused on development of an in vitro model of cell-free expressed human EGFR family of receptor tyrosine kinases, which play a role in cancer progression and treatment. Many of the works involve development of new biochemical and biophysical techniques using the nanolipoprotein particles (NLPs) platform. NLPs are 10-25nm sized disk shape particles that comprised of a scaffold and a piece of bilayer membrane. NLPs recapitulate the cell membrane environment that can support functional membrane protein. It has been demonstrated that a wide range of membrane proteins can be de novo synthesized in a functional form, including G-protein coupled protein receptors, bacteriorhodopsins, receptor tyrosine kinases and antigenic membrane proteins such as the major outer membrane protein (MOMP) from chlamydia. In addition, I have also developed novel multifunctional nanoparticle platforms for delivery of nucleic acid, protein and small molecule therapeutics for cancer treatment and vaccine development. In collaboration with Synthetic Genomics Vaccines Inc., we have recently developed cationic NLP based delivery platform for in vivo delivery of self-amplifying mRNA. Self-amplifying mRNA (replicon) has recently emerged as a great alternative to traditional protein-based therapeutics. The replicon is engineered to carry the gene of interest from the single-stranded RNA genome of alphaviruses. When in the cytoplasm of host cells, replicons can effectively propagate and maintain a high level of expression of the protein of interest over prolonged periods of time. Recently our group has demonstrated that NLPs comprised of positively charged lipids (cationic NLPs), can be formulated with RNA replicons to form stable complexes. In addition, these complexes can be effectively delivered in vivo to target tissue, resulted in persisted expression of protein at high level for up to 14 days post injection. This NLP:Repicon platform has shown great promise in becoming a safe and efficient vaccine formulation.

Besides using NLP as an effective drug delivery vehicle, I am also interested in studying membrane protein structure and function supported by NLP. Membranes proteins make up more than 60% of the current drug targets and account for approximately 30% or more of the cellular proteome. Furthermore, membrane proteins are challenging to study because of their insolubility and tendency to aggregate in aqueous solutions. Understanding membrane protein structure and function demands developing novel means of membrane protein production that preserves their native state. The use of cell-free expression systems has emerged as an important complement to cell-based expression approaches due to their simple and customizable experimental parameters. Employing NLPs to yield membrane proteins in stable, native like states has become common practice to facilitate biochemical and biophysical characterization, and NLP technology can be easily coupled with cell-free systems to achieve functional membrane protein production for this purpose. Our approach involves utilizing cell-free expression systems in the presence of NLPs or using co-translation techniques. We show how cell-free reactions can be modified to render control over nanoparticle size and monodispersity in support of membrane protein production. These aforementioned modifications have been exploited to show co-expression of full-length functional membrane proteins such as G-protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). The functionalities of the proteins are further validated through cell based reported assay and in vitro single molecule fluorescent assay. The future goal is to develop this technology to drive drug discovery against these critical targets.

In addition, my research also involves the development of engineered and instrumented 3D Tumor-Immune Model System. The 3D Tumor-Immune Model System uses precisely controlled bio-printed human tumors to help clinicians with cancer diagnostic and personalized drug discovery.

My early works were focused on expression and purification of various proteins for basic and biotechnology research. As part of my master’s degree studies, I developed a high-level expression system for human Cu-Zn superoxide dismutase in Saccharomyces cerevisiae. My research involves recombinant genetic engineering, extensive sequence comparisons and optimizations, large-scale fermentations, and optimization of protein expression and purification conditions.

 

Education

Fudan University, Shanghai, P.R.China.     Chemistry/Microbiology    B.S.,   1998

Fudan University, Shanghai, P.R.China.     Biochemistry    M.S.,   2001   

University of California, Davis    Pharmacology and toxicology     Ph.D.  2015


Appointments

2018 – present            Biomedical Scientist, Physical and Life Sciences, Lawrence Livermore National Laboratory

2015 – 2018                Postdoctoral Fellow, Physical and Life Sciences, Lawrence Livermore National Laboratory

2010 - 2015                 Graduate Student Research Associate, Radiation Oncology, University of California, Davis

2008 - 2010                 Research Specialist, The NSF Center for Biophotonics, University of California, Davis

2001 - 2003                 Project Scientist, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China

Awards

2014                            Ines McMillan Fellowship / UC Davis, Pharmacology & Toxicology

2018                            Hans Neurath Outstanding Promise Travel Award / Protein Society

 

Selected Publications

He, W., Evans, A.C., Rasley, A., Bourguet, B., Peters, P., Kamrud, K., Wang N., Hubby, B., Felderman, M., Gouvis, H., Coleman, M.A., Fischer, N.O. (2018) Cationic HDL mimetics enhance in vivo delivery of self-replicating mRNA. (Submitted under review)

*Cleveland, T.E., *He, W., Evans, A.C., Fischer, N.O., Lau, E.Y., Coleman, M.A. and Butler, P. Small-angle X-ray and neutron scattering demonstrates that cell-free expression produces properly formed disc-shaped nanolipoprotein particles. (2018) Protein Science. 27 (3), 780-789. (*Co-first author)

Quinn, S., Srinivasan, S., Gordon, J., He, W., Carraway, K. L., Coleman, M. A., Schlau-Cohen, G. S. Single-molecule fluorescence detection of the epidermal growth factor receptor (EGFR) in membrane discs. (2018) Biochemistry DOI: 10.1021/acs.biochem.8b00089

Patriarchi, T., Shen, O., He, W., Baikoghli, M., Cheng, H., Xiang, K., Coleman, M.A.  and Tian, L. Nanodelivery of a functional membrane receptor to manipulate cellular phenotype. (2018) Scientific Reports. 8 (1), 3556

He, W., Felderman, M., Evans, A.C., Geng, J., Homan, D., Bourguet, F., Fischer, N.O., Li, Y., Lam, K.S., Noy, A., Xing, L., Cheng, R.H., Rasley, A., Blanchette, C.D., Kamrud, K., Wang, N., Gouvis, H., Peterson, T.C., Hubby, B. and Coleman, M.A. Cell-free production of a functional oligomeric form of a chlamydia major outer membrane protein (MOMP) for vaccine development. (2017) J. Biol. Chem. 292 (36), 15121-15132

Scharadin, T.M., He, W., Yiannakou, Y., Tomilov, A.A., Saldana, M., Cortopassi, G.A., Carraway, K.L. 3rd, Coleman, M.A., Henderson, P.T. Synthesis and biochemical characterization of EGF receptor in a water-soluble membrane model system. (2017) PLoS One. 12(6): e0177761

He, W., Scharadin, T., Saldana, M., Gellner, M., Hoang-Phou, S., Takanishi, C., Hura, G.L., Tainer, J.A., Carraway III, K.A., Henderson, P.T., Coleman, M.A. Cell-free expression of functional receptor tyrosine kinases. (2015) Scientific Reports. 5:12896.

He, W., Luo, J., Bourguet, F., Xing, L., Yi, S., Gao, T., Blanchette, C., Henderson, P., Kuhn, E. Malfatti, M., Murphy, W., Cheng, H., Lam, K., and Coleman, M.A. Controlling the Diameter, Monodispersity and Solubility of ApoA1 Nanolipoprotein Particles using Telodendrimer Chemistry. (2013) Protein Science. 22, 1078–1086.

Gao, T., Petrlova, J., He, W., Huser, T., Kudlicki, W., Voss, J., and Coleman, M.A. Characterization of de novo synthesized GPCRs supported in nanolipoprotein discs. (2012) PloS One. 7(9): e44911.

Gao, T., Blanchette, C., He, W., Bourguet, F., Ly, S., Katzen, F., Kudlicki, W., Henderson, P.T., Laurence, T. Huser, T., and Coleman, M.A. Characterizing diffusion dynamics of a membrane protein associated with nanolipoproteins using fluorescence correlation spectroscopy. (2011) Protein Science. 20:437-47.

 

Book chapter:

Gilmore, S.F., He, W., Rasley, A., Fischer, N.O. (2017) Strategies for functionalizing lipoprotein-based nanoparticles. ACS Symposium "Control of Amphiphile Self-Assembling at the Molecular Level: Supra-Molecular Assemblies with Tuned Physicochemical Properties for Delivery Applications”