Dr Shi received his Bachelor degree in Biological Sciences from Xiamen University in 2002. After graduation, he was awarded a full PhD scholarship to join of Dr Jianxing Song’s lab at National University of Singapore. During his PhD studies, he used various structural biology methods to study the enzymatic mechanism of Severe Acute Respiratory Syndrome (SARS) coronavirus’s main protease. He determined the first inactive protease mutant crystal structure, revealing that the catalytic mechanism of the SARS protease was regulated by dimerization. To explore new areas of research and broaden his expertise, Dr Shi J.oined the laboratory of Dr Harvey Lodish, a member of the American National Academy of Science at the Whitehead Institute for Biomedical Research, to learn cell biology during a post-doctoral training. His research was to investigate important aspects of red blood cell (RBC) development and also to use RBCs for bioengineering. He discovered a new mechanism for alternative pre-mRNA splicing regulated by muscleblind-like 1 (Mbnl1) in RBC development. At the same time, he also co-invented a new technology for engineering RBCs as carriers for a wide range of therapeutic cargoes. His innovation on RBC engineering has attracted more than 10 million US dollars investment from Flagship Ventures for establishing a startup company called Rubiustx.
Dr Shi’s research focuses on both basic and applied sciences of red blood cell biology. His first aim is to investigate RBC development, which may have profound implications for treatments of anemia. Indeed, one third of the world's population suffers from anemia with enormous health and economic consequences. Despite available pharmaceuticals, RBC transfusion is still the only way to treat severe anemic patients caused by chronic cancer, infectious diseases and genetic disorders. The increased blood demands stress the public supplies. Therefore, his goal is to determine the regulatory mechanism governing RBC development as a prerequisite to develop anti-anemia therapies. His research would gain new insights into the regulation of RBC development and may reveal new ways to develop anti-anemia therapy for anemic patients, including chronic cancer patients.
His second aim is to engineer RBCs as vascular carriers for therapeutic agents. Using RBCs as drug carriers may resolve critical issues associated with drug delivery including poor solubility, poor stability, short half-life, toxicity and availability. RBCs possess many unique characteristics, including no genetic materials and long survival time (>120 days) that make them attractive candidates for vascular delivery of therapeutic cargoes. His goal is to engineer RBCs as cell-based carriers for therapeutic agents. This technology opens a new avenue for vascular drug delivery, which could potentially be useful for the diagnosis and treatment of many diseases.
PhD scholarships, undergraduate research internships and research assistant positions are available for BSc or MSc students with great interest in biomedical research. Please contact Dr Shi for further information.
- Sarah U. Morton, Sanjay P. Prabhu, Hart G.W. Lidov, Jiahai Shi, Catherine A. Brownstein, Alan H. Beggs, Sara O. Vargas, and Pankaj B. Agrawal, “AIFM1 Mutation Presenting with Fatal Encephalomyopathy and Mitochondrial Disease in an Infant”, Cold Spring Harb Mol Case Stud. Accepted
- Sarah U. Morton, Edward G. Neilan, Roy W.A. Peake, Jiahai Shi, Klaus Schmitz-Abe, Meghan Towne, Kyriacos Markianos, Sanjay P. Prabhu, Pankaj B. Agrawal, “Anapleurotic Replacement due to Purported Kreb Cycle Intermediate Deficiencies in Two Siblings with FBXL4 Variants” JIMD Reports, Accepted
- Paulomi Mehta, Melanie Küspert, Tejus Bale, Jiahai Shi, Catherine A Brownstein, Umberto De Girolami, Alan H. Beggs, Basil Darras, Michael Wegner, Xianhua Piao, and Pankaj B. Agrawal, “Novel Missense Mutation in CNTNAP1 results in Congenital Hypomyelinating Neuropathy”, Muscle and Nerve, Accepted.
- Samantha Palmer, Meghan C. Towne, Phillip L. Pearl, Renee C. Pelletier, Casie A. Genetti, Jiahai Shi, Alan H. Beggs, Pankaj B. Agrawal, and Catherine A. Brownstein, “SLC6A1 Mutation and Ketogenic Diet in epilepsy with myoclonic-atonic seizures”, Pediatric Neurology, Pediatr Neurol. 2016 Jul 28.
- Niklas Smedemark-Margulies ，Catherine A. Brownstein, Sigella Vargas, Sahil K. Tembulkar, Meghan C. Towne, Jiahai Shi, Elisa Gonzalez-Cuevas, Kevin X. Liu, Kaya Bilguvar, Robin J. Kleiman, Min-Joon Han, Alcy Torres, Gerard T. Berry, Timothy W. Yu, Alan H. Beggs, Pankaj B, Agrawal, Joseph Gonzalez-Heydrich, “A novel de novo mutation in ATP1A3 and Childhood-Onset Schizophrenia”, Cold Spring Harb Mol Case Stud. 2016 Sep;2(5)
- Jiahai Shi, Bingbing Yuan, Wenqian Hu, Harvey Lodish, “JAK2 V617F stimulates proliferation of erythropoietin- dependent erythroid progenitors and delays their differentiation by activating Stat1 and other non-erythroid signaling pathways”, Experimental Hematology, Exp Hematol. 2016 Jul 26.
- Joshi M, Anselm I, Shi J, Bale TA, Towne M, Schmitz-Abe K, Crowley L, Giani FC, Kazerounian S, Markianos K, Lidov HG, Folkerth R, Sankaran VG, Agrawal PB, “Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-alpha protein (PMPCA) cause a severe mitochondrial disease”, Cold Spring Harb Mol Case Stud. 2016 May;2(3):a000786. doi: 10.1101/mcs.a000786.
- Brownstein CA, Beggs AH, Rodan L, Shi J, Towne MC, Pelletier R, Cao S, Rosenberg PA, Urion DK, Picker J, Tan WH, Agrawal PB, “Clinical heterogeneity associated with KCNA1 mutations include cataplexy and non-ataxic presentations”, Neurogenetics. 2016 Jan;17(1):11-6. doi: 10.1007/s10048-015-0460-2.
- Li H*, Shi J*, Huang NJ, Pishesha N, Natarajan A, Eng JC, Lodish HF, “Efficient CRISPR-Cas9 mediated gene disruption in primary erythroid progenitor cells”, Haematologica. 2016 Jun;101(6):e216-9. doi: 10.3324/haematol.2015.135723. *: Equal contribution
- Jiahai Shi*, Lenka Kundrat*, Novalia Pishesha, Angelina Bilate, Chris Theile, Takeshi Maruyama, Stephanie K. Dougan, Hidde Ploegh, and Harvey Lodish, “Engineered red cells as carriers for systemic delivery of a wide array of functional probes”, Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10131-6. *: Equal contribution
- Featured in "In This Issue" by the editorial board of PNAS
- Highlighted in Science News, New Scientist, PBS NOVA and 11 other news reports
- Albert W. Cheng*, Jiahai Shi*, Piu Wong*, Katherine K. Luo, Paula Trepman, Eric T. Wang, Christopher B. Burge, and Harvey F. Lodish, “Mbnl1 regulates alternative RNA splicing in terminal erythropoiesis”, Blood. 2014 Jul 24;124(4):598-610., *: Equal contribution
- Commented in Don M. Wojchowski, Erythroid mRNA processing: a "splice of life", Blood. 2014 Jul 24;124(4):474-5.
- Lim L.*, Shi J.*, Mu Y., Song J., “Dynamically-Driven Enhancement of the Catalytic Machinery of the SARS 3C-Like Protease by the S284-T285-I286/A Mutations on the Extra Domain.” PLoS One. 2014 Jul 18;9(7) *: Equal contribution
- Huan X.*, Shi J.*, Lim L.*, Mitra S., Zhu W., Qin H., Pasquale E.B., Song J., “Unique structure and dynamics of the EphA5 ligand binding domain mediate its binding specificity as revealed by X-ray crystallography, NMR and MD simulations.” PLoS One. 2013 Sep 24;8(9) *: Equal contribution
- Shi J.*, Han N.*, Lim L., Lua S., Sivaraman J., Wang L., Mu Y., Song J., ‘Dynamically-Driven Inactivation of the Catalytic Machinery of the SARS 3C-Like Protease by the N214A Mutation on the Extra Domain,’ PLoS Comput Biol (2011) 7(2) *: Equal contribution
- Shi J., Sivaraman J., Song J., ‘Mechanism for Controlling Dimer-Monomer Switch and Coupling Dimerization to Catalysis of the SARS-CoV 3C-like protease,’ Journal of Virology, (2008) 82(9):4620-9
- Shi J.*, Lua S.*, Du N., Liu X., Song J., ‘Identification, recombinant production and structural characterization of four silk proteins from the Asiatic honeybee Apis cerana,’ Biomaterials, (2008) 29(18):2820-8 *: Equal contribution
- Qin H.*, Shi J.*, Noberini R., Pasquale B.E., Song J., ‘Crystal Structure and NMR Binding Reveal that Two Small Molecule Antagonists Target the High-Affinity Ephrin-Binding Channel of the EphA4 Receptor,’ J Biol Chem. (2008) 283:29473-84 *: Equal contribution
- Shi J.*, Lua S.*, Tong J., Song J., ‘Elimination of the Native Structure and Solubility of the hVAPB MSP Domain by the Pro56Ser Mutation which Causes Amyotrophic Lateral Sclerosis’ Biochemistry. (2010) 49(18):3887-97 *: Equal contribution
- Shi J and Song J, ‘The catalysis of the SARS 3C-like protease is under extensive regulation by its extra domain’, FEBS Journal (2006) 273:1035–45
- Shi J, Wei Z, Song J, ‘Dissection study on the SARS 3C-like protease reveals the critical role of the extra domain in dimerization of the enzyme: Defining the extra domain as a new target for design of highly-specific protease inhibitors’, J Biol Chem. (2004) 279:24765-73
- Heide Christine Patterson, Carolin Gerbeth, Prathapan Thiru, F.-Nora Voegtle, Marko Knoll, Aliakbar Shahsafaei, Kaitlin E. Samocha, Cher X. Huang, Mark M. Harden, Rui Song, Cynthia Chen, Jennifer Kao, Jiahai Shi, Wendy Salmon, Yoav D. Shaul, Matthew P. Stokes, Jeffrey C. Silva, George W. Bell, Daniel G. MacArthur, Juergen Ruland, Chris Meisinger, Harvey F. Lodish, “A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates H2O2 signaling” PNAS, online the week of October 5, 2015.
- Vijay G. Sankaran, Jacob C. Ulirsch, Vassili Tchaikovskii, Leif S. Ludwig, Aoi Wakabayashi, Senkottuvelan Kadirvel, R. Coleman Lindsley, Rafael Bejar, Jiahai Shi, Scott B. Lovitch, David F. Bishop, David P. Steensma, “X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation”, Journal of Clinical Investigation, 2015 Apr;125(4):1665-9.
- Shilpa M. Hattangadi, Sandra Martinez-Morilla, Heide Christine Christine Patterson, Jiahai Shi, Karly A Burke, Amalia Avila Figueroa, Srividhya Venkatesan, Junxia Wang, Katherina Paulsen, Cher Huang, Dirk Gorlich, Maki Murata-Hori, and Harvey F Lodish, “Histones to the cytosol: Exportin 7 plays an important role in terminal erythroid nuclear maturation,” Blood. 2014 Aug 4. pii: blood-2013-11-537761.
- Pishesha N., Thiru P., Shi J., Eng J.C., Sankaran V.G., Lodish H.F., “Transcriptional divergence and conservation of human and mouse erythropoiesis”, Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4103-8.
- Alvarez-Dominguez J.R., Hu W., Yuan B., Shi J., Park S.S., Gromatzky A.A., van Oudenaarden A., Lodish H.F., “Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation”, Blood. 2014 Jan 23;123(4):570-81
- Lua S., Qin H., Lim L., Shi J., Gupta G., Song J., ‘Structural, stability, dynamic and binding properties of the ALS-causing T46I mutant of the hVAPB MSP domain as revealed by NMR and MD simulations.’ PLoS One. (2011) 6(11)
- Shaveta G., Shi J., Chow VT, Song J., ‘Structural characterization reveals that viperin is a radical S-adenosyl-L-methionine (SAM) enzyme,’ Biochem Biophys Res Commun. (2010) 391(3):1390-5
- Qin H., Noberini R., Huan X., Shi J., Pasquale EB, Song J., ‘Structural characterization of the EphA4-Ephrin-B2 complex reveals new features enabling Eph-ephrin binding promiscuity,’ J Biol Chem. (2010) 285(1):644-54
- Ran X., Qin H., Liu J., Fan J., Shi J., Song J., ‘NMR structure and dynamics of human ephrin-B2 ectodomain: The functionally critical C-D and G-H loops are highly dynamic in solution,’ Proteins: Structure, Function, and Bioinformatics (2008) 72:1019-29
- Li M, Liu J, Ran X, Fang M, Shi J, Qin H, Goh J, Song J, ‘Resurrecting Abandoned Proteins with Pure Water: CD and NMR Studies of Protein Fragments Solubilized in Salt-Free Water’ Biophysics J. (2006) 91(11):4201-9
- Li M, Shi J, Wei Z, Teng FY, Tang BL, Song J, ‘Structural characterization of the human Nogo-A functional domains’, Eur J Biochem. (2004) 271:3512-22