Lee Rubin, Ph.D.
Principal Faculty, Harvard Stem Cell Institute
Lee Rubin investigates the key molecular mediators of neurodegenerative diseases, with the ultimate goal of finding effective preclinical therapeutic candidates.
Dr. Rubin obtained his Ph.D. in Neuroscience from The Rockefeller University and completed postdoctoral fellowships in Pharmacology from Harvard Medical School and in Neurobiology from Stanford University School of Medicine. He has a broad experience in both academia and industry, particularly in the realms of cell-based assays and drug discovery. Prior to coming to Harvard, he was Chief Scientific Officer of Curis, Inc., a Cambridge-based biotechnology company, where his group identified the first small molecule regulators of the hedgehog signaling pathway. One of their antagonists was developed by Genentech and is now (as Erivedge) approved as the first oral treatment for metastatic basal cell carcinoma.
At Harvard, much of his work is focused on finding key molecular mediators of different neurodegenerative diseases and on searching for effective preclinical therapeutic candidates. His group's research takes advantage of their ability to produce large numbers of patient-derived induced pluripotent stem cell lines and of effective means of deriving large numbers of differentiated neurons from them. They have set up an array of techniques that allow them to identify early cellular and physiological changes in neurons as they become diseased. For example, they have identified new targets for the treatment of the motor neuron disorders Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis. They are also studying Autism Spectrum Disorders, Parkinson’s disease and Alzheimer’s disease.
Recently, his group discovered that a circulating protein, GDF11, has the ability to reverse some of the changes in the CNS associated with aging. They are actively exploring the therapeutic implications of these observations as well.
- Ng S-Y, Soh BS, Rodriguez-Muela N, Hendrickson DG, Price F, Rinn JL, Rubin LL. Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy. Cell Stem Cell 2015; 17:569-84. PMCID: PMC4839185.
- Wainger BJ, Buttermore ED, Oliveira JT, Mellin C, Lee S, Saber WA, Wang A, Ichida JK, Chiu IM, Barrett L, Huebner EA, Bilgin C, Tsujimoto N, Brenneis C, Kapur K, Rubin LL, Eggan K, Woolf CJ. Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nat Neurosci 2015; 18:17-24.
- Schlaeger, TM, Daheron L, Brickler TR, Entwisle S, Chan K, Cianci A, DeVine A, Ettenger A, Fitzgerald K, GodfreyM, Gupta D, McPherson J, Malwadkar P, Doi A, Jung N, Li X, Lynes MS, Brookes E, CherryABC, Demirbas D, TsankovA, Zon LI, Rubin LL, Feinberg AP, Meissner A, Cowan CA, and Daley GQ. A comparison of non-integrating reprogramming methods. Nature Biotech 2015; 33:58-63.
- Woodard CM, Campos BA, Kuo S-H, Nirenberg MJ, Nestor MW, Zimmer M, Mosharov E, Sulzer D, Zhou H, Paull D, Clark L, Schadt EE, Sardi SP, Rubin L, Eggan K, Brock M, Lipnick S, Rao M, Chang S, Li A, Noggle SA. iPSC-Derived Dopamine Neurons Reveal Differences between Monozygotic Twins Discordant for Parkinson’s Disease. Cell Reports 2014; 9:1-10.
- Blum B, Roose AN, Barrandon O, Maehr R, Arvanites AC, Davidow LS, Davis JC, Peterson QP, Rubin LL, Melton DA. Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway. eLife 2014; 3:e02809. PMCID: PMC4204634.
- Cherry JJ, Kobayashi DT, Lynes MM, Naryshkin NN, Tiziano FD, Zaworski PG, Rubin LL, Jarecki J. Assays for the identification and prioritaztion of drug candidates for spinal muscular atrophy. Assay Drug Dev Technol 2014; 12:315-41.
- Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X, Feng Z, Ling KK, Karp GM, Qi H, Woll MG, Chen G, Zhang N, Gabbeta V, Vazirani P, Bhattacharyya A, Furia B, Risher N, Sheedy J, Kong R, Ma J, Turpoff A, Lee CS, Zhang X, Moon YC, Trifillis P, Welch EM, Colacino JM, Babiak J, Almstead NG, Peltz SW, Eng LA, Chen KS, Mull JL, Lynes MS, Rubin LL, Fontoura P, Santarelli L, Haehnke D, McCarthy KD, Schmucki R, Ebeling M, Sivaramakrishnan M, Ko CP, Paushkin SV, Ratni H, Gerlach I, Ghosh A, Metzger F. Motor neuron disease: SMN2 splicing modifiers improve motor function and longevity in mice and spinal muscular atrophy. Science 2014; 345:688-93. PMID: 25104390.
- Gould SE, Low JA, Marsters JC Jr, Robarge K, Rubin LL, de Sauvage FJ, Sutherlin DP, Wong H, Yauch RL. Discovery and preclinical development of vismodegib. Expert Opin Drug Discov 2014; 9:969-84.
- Ichida JK, TCW J, Williams LA, Carter AC, Shi Y, Moura MT, Ziller M, Singh S, Amabile G, Bock C, Umezawa A, Rubin LL, Bradner JE, Akutsu H, Meissner A, Eggan K. Notch inhibition allows oncogene-independent generation of iPS cells. Nat Chem Biol 2014; 10:632-9.
- Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014; 344:630-4. PMCID: PMC4123747.
- Sen A, Dimlich DN, Guruharsha KG, Kankel MW, Hori K, Yokokura T, Brachat S, Richardson D, Loureiro J, Sivasankaran R, Curtis D, Davidow LS, Rubin LL, Hart AC, Van Vactor D, Artavanis-Tsakonas S. Genetic Circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy. Proc Acad Natl Sci U S A 2013; 110:E2371-80. PMCID: PMC3696827.
- Yang YM, Gupta SK, Kim KJ, Powers BE, Cerqueira A, Wainger BJ, Ngo HD, Rosowski KA, Schein PA, Ackeifi CA, Arvanites AC, Davidow LS, Woolf CJ, Rubin LL. A Small Molecule Screen in Stem Cell-derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS. Cell Stem Cell 2013; 12:713-26. PMCID: PMC3707511.
- Ding HQ, Lee YK, Schaefer EA, Peters DT, Veres A, Kim K, Kuperwasser N, Motola DL, Meissner TB, Hendriks WT, Trevisan M, Gupta RM, Moisan A, Banks E, Friesen M, Schinzel RT, Xia F, Tang A, Xia Y, Figueroa E, Wann A, Ahfeldt T, Daheron L, Zhang F, Rubin LL, Peng LF, Chung RT, Musunuru K, Cowan CA. A Talen Genome-Editing System for Generating Human Stem Cell-Based Disease Models. Cell Stem Cell 2013; 12:238-51. PMCID: PMC3570604.
- Wang Y, Davidow L, Arvanites AC, Blanchard J, Lam K, Xu K, Oza V, Yoo JW, Ng JMY, Curran T, Rubin LL, McMahon AP. Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity. Chem Biol 2012; 19:972-82. PMCID: PMC3724998.
- Hayhurst, M, Wagner A, Cerletti M, Wagers AJ, Rubin LL. A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of Survival of Motor Neuron protein. Dev Biol 2012; 368:323-34. PMCID: PMC3851302.
- Wang, Yu, Arvanites AC, Davidow L, Blanchard J, Lam K, Yoo JW, Coy S, Rubin LL, McMahon, AP. Selective Identification of Hedgehog Pathway Antagonists By Direct Analysis of Smoothened Ciliary Translocation. ACS Chem Bio 2012; 7:1040-8. PMCID: PMC3905677.
- Chen PC, Gaisina IN, El-Khodor BF, Ramboz S, Makhortova NR, Rubin LL, Kozikowski AP. Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, that Prolongs the Median Survival Time of ∆7 SMA KO Mouse Model of Spinal Muscular Atrophy. ACS Chem Neurosci 2012;3:5-11. PMCID: PMC3279955.
- Annes JP, Ryu JH, Lam K, Carolan PJ, Utz K, Hollister-Lock J, Arvanites AC, Rubin LL, Weir G, Melton DA. Adenosine kinase inhibition selectively promotes rodent and porcine islet ß-cell replication. Proc Natl Acad Sci U S A 2012; 109:3915-20. PMCID: PMC3309788.
- Makhortova NR, Hayhurst M, Cerqueira A, Sinor-Anderson A, Zhao W-N, Heiser P, Arvanites AC, Davidow LS, Waldon ZO, Steen JA, Lam K, Ngo H, Rubin LL. A Screen for Regulators of Survival of Motor Neuron Protein Levels. Nature Chem Biol 2011; 7:544-52. PMCID: PMC3236614.
- Tang JY, Li D, Reich M, Callahan CA, Fu L, Yauch RL, Wang F, Kotkow K, Chang KS, Shpall E, Wu A, Rubin LL, Marsters JC, Epstein EH, Caro I, de Sauvage FJ. Targeting Superficial or Nodular Basal Cell Carcinoma with Topically Formulated Small Molecule Inhibitor of Smoothened. Clinical Cancer Research 2011; 17:3378-87.
- Rubin LL, Haston KM. Stem cells and drug discovery. BMC Biol2011; 9:42. PMCID: PMC3110139.
- Haramati S, Chapnik E, Sztainberg Y, Eilam R, Zwang R, Gershoni N, McGlinn E, Heiser PW, Wills AM, Wirguin I, Rubin LL, Misawa H, Tabin CJ, Brown R Jr, Chen A, Hornstein E. miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A 2010; 107:13111-6. PMCID: PMC2919953.
- Rihel J, Prober DA, Arvanites A, Lam K, Zimmerman S, Haggarty S, Rubin LL, Peterson RT, Schier AF. (2010). Behavioral profiling links drugs to biological targets and the regulation of rest/wake states. Science, 327:348-51. PMCID: PMC2830481.
- Ichida JK*, Blanchard J*, Lam K*, Son EY*, Chung, JE, Dieter E, Loh KM, Carter AC, Di Girogio FP, Koszka K, Huangfu D, Huangfu D, Akutsu H, Liu DR, Rubin LL+, Eggan K+. A Small Molecule Inhibitor of Tfg-ß Signaling Replaces Sox2 in Reprogramming by Inducing Nanog. Cell Stem Cell 2009; 5:491-503. (* joint first authors; + joint senior authors). PMCID: PMC3335195.
- Chen S, Borowiak M, Fox JL, Maehr R, Osafune K, Davidow L, Lam K, Peng LF, Schreiber SL, Rubin LL, Melton DM. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nature Chem Biol 2009; 5:258-65. PMID: 19287398.
- Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters JC, Rubin LL, de Sauvage FJ. A paracrine requirement for hedgehog signaling in cancer. Nature 2008; 455:406-10. PMID: 18754008.
- Rubin LL. Stem Cell and drug discovery: The beginning of a new era? Cell 2008; 132:549-52.
- Brunton SA, Stibbard JH, Rubin LL, Kruse LI, Guicherit OM, Boyd EA, Prince S. Potent Inhibitors of the Hedgehog signaling pathway. J Med Chem 2008; 51:1108-10.
- Williams JA, Guicherit OM, Zaharian BI, Xu Y, Chai L, Wichterle H, Kon C, Gatchalian C, Porter JA, Rubin LL, Wang FY. Identification of a small molecule inhibitor of the hedgehog signaling pathway: Effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci 2003; 100:4616-21. PMCID: PMC153604.
- Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H, Bumcrot D, Wang FY, Jones S, Shulok J, Rubin LL, Porter JA. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol 2002; 1:10. PMCID: PMC137065.