Welcome to the Schultz Lab

The focus of our research is the biologically inspired synthesis of molecules and molecular assemblies with novel physical, chemical or biological properties. Although chemists are quite sophisticated in their ability to synthesize complex molecular architectures, our ability to rationally design and synthesize molecules with a desired molecular function is still in its infancy. Nature, on the other hand, has generated a vast array of molecules with remarkable properties — from the antibody molecule and enzymes to the photosynthetic center. Given Nature's "synthetic" prowess, we have undertaken an approach to synthesis in which the molecules, biosynthetic machinery and strategies of living organisms are combined with the principles and tools of physical organic and synthetic chemistry to create molecules with new functions difficult to generate by either approach alone. By studying the properties of the resulting molecules, new insights are gained into the molecular mechanisms of complex biological and chemical systems.

The above theme runs throughout all of the projects in the lab. Current efforts focus on: (1) the development and application of general methods to add unnatural amino acids with novel chemical, biological, and physical properties to the genetic codes of living organisms; (2) the application of combinatorial methods to the generation of small molecules, proteins, nucleic acids, and even solid state materials with novel properties; (3) the application of chemical and genomics tools to better understand and ultimately control (both in vitro and in vivo) the biological processes involved in stem cell self renewal, differentiation and cellular reprogramming; (4) early stage translational research focused on regenerative medicine, cancer, autoimmune, metabolic, and orphan/neglected diseases; and (5) the generation of catalytic antibodies and the characterization of their mechanisms and immunological evolution.

Group Information

The group occupies 10,000 square feet of laboratory space in the Stein Clinical Research Center, adjacent to the Beckman Center for Chemical Sciences. The lab currently consists of roughly 25 graduate students, postdoctoral fellows, and staff. Coworkers typically go on to careers in academics, biotech or the pharmaceutical industry (past group members are on the faculties of 85+ research universities around the world).

Representative Publications

1. Liu, C.C., Mack, A.V., Tsao, M-L., Mills, J.H., Lee, H., Choe, H., Farzan, M., Schultz, P.G., Smider, V.V. "Protein evolution with an expanded genetic code." Proc. Natl. Acad. Sci., 105(46):17688-93, 2008.
2. Wu, X., Schultz, P.G. "Synthesis at the interface of chemistry and biology." J. Am. Chem. Soc., 131(35):12497-515, 2009.
3. Wurdak, H., Romero, A., Zhu, S., Lorger, M., Watson, J., Chiang, C., Zhang, J., Natu, V.S., Tu, B.P., Walker, J., Harsh, G.R., Felding-Habermann, B., Orth, A.P., Miraglia, L.J., Rines, D.R., Skirboll, S.L., Schultz, P.G. "An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation." Cell Stem Cell, 6(1):37-47, 2010.
4. Liu, C.C., Schultz, P.G. "Adding new chemistries to the genetic code." Ann. Rev Biochem, 79:413-44, 2010.
5. Boitano, A.E., Wang, J., Romeo, R., Bouchez, L.C., Parker, A., Sutton, S., Walker, J.R., Tellew, J., Denision, M., Cooke, M.P., Schultz, P.G. "Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells." Science, 329(5997):1345-8, 2010.
6. Wurdak, H., Zhu, S., Min, K.H., Aimone, L., Lairson, L.L., Watson, J., Chopiuk, G., Demas, J., Charette, B., Halder, R., Weerapana, E., Cravatt, B.F., Cline, H.T., Peters, E.C., Zhang, J., Walker, J.R., Wu, C., Chang, J., Tuntland, T., Cho, C.Y., Schultz, P.G. "A small molecule accelerates neuronal differentiation in the adult rat." Proc. Nat. Acad. Sci., 107(38):16542-7, 2010.
7. Lyssiotis, C.A., Lairson, L.L., Boitano, A.E., Wurdak, H., Zhu, S., Schultz, P.G. "Chemical control of stem cell fate and developmental potential." Angew. Chem., 50(1):200-42, 2011.
8. Young, T.S., Young. D.D., Ahmad, I., Louis, J.M., Benkovic, S.J., Schultz, P.G. "The evolution of cyclic peptide protease inhibitors." Proc. Nat. Acad. Sci., 108(27):11052-11056, 2011.
9. Gauba, V., Grunewald, J., Gorney, V., Deaton, L., Kang, M., Bursulaya, B., Ou, W., Lerner, R.A., Schmedt, C., Geierstanger, B.H., Schultz, P.G., Ramirez-Montagut, T. "Loss of CD4 T-cell dependent tolerance to proteins with modified amino acids." Proc. Nat. Acad. Sci., 108(31):12821-6, 2011.
10. Liu, J., Johnson, K., Li, J., Piamonte, V., Steffy, B.M., Hsieh, M., Ng, N., Zhang, J., Walker, J.R., Ding, S., Muneoka, K., Wu, X., Glynne, R., Schultz, P.G. "A regenerative phenotype in mice with a point mutation in TGFBR1." Proc. Nat. Acad. Sci., 108(35):14560-5, 2011.
11. Johnson, K., Zhu, S., Tremblay, M., Payette, J.N., Wang, J., Bouchez, L.C., Meeusen, S., Althage, A., Cho, C., Wu, X., Schultz, P.G. "A stem cell-based approach to cartilage repair." Science, 336(6082):717-2, 2012.
12. Kim, C., Axup, J.Y., Dubrovska, A., Kazane, S.A., Hutchins, B.A., Wold, E., Smider, V.V., Schultz, P.G. "Synthesis of bispecific antibodies with genetically encoded unnatural amino acids." J. Am. Chem. Soc., 134(24):9918-21, 2012.
13. Chatterjee, A., Xiao, H., Schultz, P.G., "Evaluation of multiple, mutually orthogonal prolyl-tRNA synthetase/tRNA pairs for unnatural amino acid mutagenesis in Escherichia coli."" Proc. Nat. Acad. Sci., 109(37):14841-6, 2012.
14. Hirota, T., Lee, J.W., St. John., P.C., Sawa, M., Iwaisako, K., Noguchi, T., Pongsawakul, P.Y., Sonntag, T., Welsh, D.K., Brenner, D.A., Doyle, J., Schultz, P.G., Kay, S.A. "Identification of small molecule activators of cryptochrome." Science, 337(6098):1094-1097, 2012.
15. Axup, J.A., Bajjuri, K.M., Ritland, M., Hutchins, B.M., Kim, C., Kazane, S.A., Halder, R., Forsyth, J.S., Santidrian, A.F., Stafin, K., Liu, Y., Tran, H., Seller, A.J., Biroc, S.L., Szydlik, A., Pinkstaff, J.K., Tian, F., Sinha, S.C., Felding-Habermann, B., Smider, V.V., Schultz, P.G. "Synthesis of site-specific antibody-drug conjugates using unnatural amino acids." Proc. Nat. Acad. Sci., 109(40):16101-16106, 2012.
16. Shen, W., Tremblay, M.S., Deshmukh, V.A., Wawng, W., Filipi, C.M., Harb, G., Zhang, Y., Kamireddy, A., Baaten, J.E., Jin, Q., Wu, T., Swoboda, J.G., Cho, C.Y., Laffitte, B.A., McNamara, P., Glynne, R., Wu, X., Herman, A.E., Schultz, P.G., "A small molecule inducer of beta cell proilferation indentified by high-throughput screening."" J. Am. Chem. Soc., 135(5):1669-72, 2013.
17. Wang, F., Sen, S., Zhang, Y., Ahmad, I., Zhu, X., Wilson, I.A., Smider, V.V., Magliery, T.J., Schultz, P.G. "Somatic hypermutation maintains antibody thermodynamic stability during affinity maturation." Proc. Nat. Acad. Sci., 110(11):4261-6, 2013.
18. Wang, F., Sambandan, D., Halder, R., Wang, J., Batt, S., Weinrick, B.C., Ahmad, I., Yang, P., Zhang, Y., Kim, J., Hassani, M., Huszar, S., Trefzer, C., Chatterjee, A., Johnsson, K., Mikusove, K., Besra, G., Futterer, K., Jacobs, W.R., Schultz, P.G. "Identification of a small molecule with activity against drug-resistent and persistent tuberculosis." Proc. Nat. Acad. Sci., 110(27):E2510-7, 2013.
19. Chatterjee, A., Xiao, H., Bollong, M., Ai, H., Schultz, P.G., "An efficient viral delivery system for unnatural amino acid mutagenesis in mammalian cells."" Proc. Nat. Acad. Sci., 110(29):11803-8, 2013.
20. Zhang, Y., Wang, D., Lichtervelde, L., Sun, S.B., Smider, V.V., Schultz, P.G., Wang, F., "Functional antibody CDR3 fusion proteins with enhanced pharmacological properties." " Angew Chem Int Ed Engl., 5;52(32):8295-8, 2013.
21. Chatterjee, A., Guo., J., Lee, H., Schultz, P., "A genetically encoded fluorescent probe in mammalian cells."" J. Am. Chem. Soc., 135(34):12540-3, 2013.
22. Deshmukh, V.A., Lyssiotis, C.A., Tardif, V., Swoboda, J., Ahmad, I., Kondo, T., Theofilopoulos, A.N., Lawson, B.R., Lairson, L.L., Schultz, P.G. " A regenerative approach to the treatment of multiple sclerosis." Nature, 502(7471):327-32, 2013..
23. Lajoie, M.J., Rovner. A.J., Goodman, D.B., Aerni, H., Mercer, J.A., Wang, H.H., Carr, P.A., Schultz, P.G., Jacobson, J.M., Rinehart, J., Church, G.M., Isaacs, F.J., "Genomically recoded organisms expand biological functions." Science, 342(6156):357-60, 2013.
24. Kim, C., Axup, J.Y., Lawson, B., Yun, H., Tardif, V., Choi, S., Zhou, Q., Dubrovska, A., Biroc, S.L., Marsden, R., Pinkstaff, J., Smider, V.V., Schultz, P.G., "A bispecific small molecule antibody conjugate targeting prostate cancer." " Proc. Nat. Acad. Sci., 110(44):17796-801, 2013.
25. Liu, T, Liu Y, Wang Y, Hull M, Schultz P, Wang F., "Rational Design of CXCR4 Specific Antibodies with Elongated CDRs." " J. Am. Chem. Soc., 136(30):10557-60, 2014.
26. Kularatne, S., Deshmukh, V., Ma, J., Tardif, V., Lim, R., Pugh, H., Sun, Y., Manibusan, A., Sellers, A., Barnett, R., Srinagesh, S., Forsyth, J.S., Hassenpflug, W., Tian, F., Javashishvili, T., Felding-Habermann, B., Lawson, B.R., Kazane, S., Schultz, P.G., "A CXCR4-Targeted Site-Specific Antibody-Drug Conjugate." " Angew Chem Int Ed Engl., in press, 2014.