Se-Jin Lee

CONTACT INFORMATION:

Johns Hopkins University School of Medicine Department of Molecular Biology and Genetics PCTB 803 725 North Wolfe Street Baltimore, Maryland 21205 phone: (410) 614-0198 FAX: (410) 614-7079 email: [email protected] website: http://www.jhu.edu/sejinlee/

PERSONAL:

Birthplace: Seoul, South Korea (born October 20, 1958) Citizenship: United States Spouse: Emily L. Germain-Lee, M.D. (married June 23, 1985) Child: Benjamin C.G. Lee (born November 6, 1994)

EDUCATION:

1981 AB, Harvard College (summa cum laude, Biochemical Sciences) 1989 MD and PhD, Johns Hopkins University School of Medicine (Molecular Biology and Genetics; PhD advisor—Daniel Nathans)

PROFESSIONAL APPOINTMENTS:

1981 Medical Scientist Training Program, Johns Hopkins University School of Medicine 1989 Staff Associate, Carnegie Institution of Washington, Department of Embryology 1991 Assistant Professor, Johns Hopkins University School of Medicine, Department of Molecular Biology and Genetics 1997 Associate Professor, Johns Hopkins University School of Medicine, Department of Molecular Biology and Genetics 2001 Professor, Johns Hopkins University School of Medicine, Department of Molecular Biology and Genetics

HONORS:

1981 summa cum laude, Harvard College 2010 Fellow (Elected), American Association for the Advancement of Science (AAAS)

ORIGINAL RESEARCH PUBLICATIONS: Daniel Linzer, Se-Jin Lee, Linda Ogren, Frank Talamantes, and Daniel Nathans (1985) Identification of proliferin mRNA and protein in mouse placenta. Proc. Natl. Acad. Sci., USA 82:4356-4359. [PMID: 3859868]

Se-Jin Lee and Daniel Nathans (1987) Secretion of proliferin. Endocrinology 120:208-213. [PMID: 3780559]

Se-Jin Lee and Daniel Nathans (1988) Proliferin secreted by cultured cells binds to mannose-6- phosphate receptors. J. Biol. Chem. 263:3521-3527. [PMID: 2963825]

Se-Jin Lee, Frank Talamantes, Elizabeth Wilder, Daniel Linzer, and Daniel Nathans (1988) Trophoblastic giant cells of the mouse placenta as the site of proliferin synthesis. Endocrinology 122:1761-1768. [PMID: 3359962]

Se-Jin Lee (1990) Expression of HSP86 in male germ cells. Mol. Cell. Biol. 10:3239-3242. [PMID: 2342473]

Se-Jin Lee (1990) Identification of a novel member (GDF-1) of the transforming growth factor-ß superfamily. Mol. Endocrinol. 4:1034-1040. [PMID: 1704486]

Se-Jin Lee (1991) Expression of growth/differentiation factor-1 in the nervous system: Conservation of a bi-cistronic structure. Proc. Natl. Acad. Sci., USA 88:4250-4254. [PMID: 2034669]

Alexandra C. McPherron and Se-Jin Lee (1993) GDF-3 and GDF-9: Two new members of the transforming growth factor-ß superfamily containing a novel pattern of cysteines. J. Biol. Chem. 268:3444-3449. [PMID: 8429021]

Elaine E. Storm, Thanh V. Huynh, Neal G. Copeland, Nancy A. Jenkins, David M. Kingsley, and Se-Jin Lee (1994) Limb alterations in brachypodism mice due to mutations in a new member of the TGF-ß superfamily. Nature 368:639-643. [PMID: 8145850]

Sharon A. McGrath, Aurora F. Esquela, and Se-Jin Lee (1995) Oocyte-specific expression of growth/differentiation factor-9. Mol. Endocrinol. 9:131-136. [PMID: 7760846]

Noreen S. Cunningham, Nancy A. Jenkins, Debra J. Gilbert, Neal G. Copeland, A. Hari Reddi, and Se-Jin Lee (1995) Growth/Differentiation Factor-10: A new member of the transforming growth factor-ß superfamily related to bone morphogenetic protein-3. Growth Factors 12:99-109. [PMID: 8679252]

Alexandra C. McPherron, Ann M. Lawler, and Se-Jin Lee (1997) Regulation of skeletal muscle mass in mice by a new TGF-ß superfamily member. Nature 387:83-90. [PMID: 9139826]

Aurora F. Esquela, Teresa A. Zimmers, Leonidas G. Koniaris, James V. Sitzmann, and Se-Jin Lee (1997) Transient down-regulation of inhibin-ßC expression following partial hepatectomy. Biochem. Biophys. Res. Comm. 235:553-556. [PMID: 9207194]

Alexandra C. McPherron and Se-Jin Lee (1997) Doubling muscling in cattle due to mutations in the myostatin gene. Proc. Natl. Acad. Sci., USA 94:12457-12461. [PMID: 9356471]

Alexandra C. McPherron, Ann M. Lawler, and Se-Jin Lee (1999) Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor-11. Nature Genet. 22:260-264. [PMID: 10391213]

Renbin Zhao, Ann M. Lawler, and Se-Jin Lee (1999) Characterization of GDF-10 expression patterns and null mice. Dev. Biol. 212:68-79. [PMID: 10419686]

Christopher T. Rankin, Tracie Bunton, Ann M. Lawler, and Se-Jin Lee (2000) Regulation of left- right patterning in mice by growth/differentiation factor-1. Nature Genet. 24:262-265. [PMID: 107— 179]

Edward C. Hsiao, Leonidas G. Koniaris, Teresa A. Zimmers-Koniaris, Suzanne M. Sebald, Thanh Huynh, and Se-Jin Lee (2000) Characterization of growth/differentiation factor-15 (Gdf15): a TGF-ß superfamily member induced following liver injury. Mol. Cell. Biol. 20:3742-3751. [PMID: 10779363]

Se-Jin Lee and Alexandra C. McPherron (2001) Regulation of myostatin activity and muscle growth. Proc. Natl. Acad. Sci., USA 98:9306-9311. [PMID: 11459935]

Alexandra C. McPherron and Se-Jin Lee (2002) Suppression of body fat accumulation in myostatin- deficient mice. J. Clin. Invest. 109:595-601. [PMID: 11877467]

Teresa A. Zimmers, Monique V. Davies, Leonidas G. Koniaris, Paul Haynes, Aurora F. Esquela, Kathy N. Tomkinson, Alexandra C. McPherron, Neil M. Wolfman, and Se-Jin Lee (2002) Induction of cachexia in mice by systemically administered myostatin. Science 296:1486-1488. [PMID: 12029139]

Kathryn R. Wagner, Alexandra C. McPherron, Nicole Winik, and Se-Jin Lee (2002) Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann. Neurol. 52:832-836. [PMID: 12447939]

Aurora F. Esquela and Se-Jin Lee (2003) Regulation of metanephric kidney development by growth/differentiation factor 11. Dev. Biol. 257:356-370. [PMID: 12729564]

Neil M. Wolfman, Alexandra C. McPherron, William N, Pappano, Monique V. Davies, Kening Song, Kathleen N. Tomkinson, Jill F. Wright, Liz Zhao, Suzanne M. Sebald, Daniel S. Greenspan, and Se-Jin Lee (2003) Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proc. Natl. Acad. Sci., USA 100:15842-15846. [PMID: 14671324]

Markus Schuelke, Kathryn R. Wagner, Leslie Stolz, Christoph Hubner, Thomas Riebel, Wolfgang Komen, Thomas Braun, James F. Tobin, and Se-Jin Lee (2004) Gross muscle hypertrophy in a child associated with a myostatin (GDF-8) mutation. New Engl. J. Med. 350:2682-2688. [PMID: 15215484]

Se-Jin Lee, Lori A. Reed, Monique V. Davies, Stefan Girgenrath, Mary E.P. Goad, Kathy N. Tomkinson, Jill F. Wright, Christopher Barker, Gregory Ehrmantraut, James Holmstrom, Betty Trowell, Barry Gertz, Man-Shiow Jiang, Suzanne M. Sebald, Martin Matzuk, En Li, Li-fang Liang, Edwin Quattlebaum, Ronald L. Stotish, and Neil M. Wolfman (2005) Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc. Natl. Acad. Sci., USA 102:18117-18122. [PMID: 16330774] Se-Jin Lee (2007) Quadrupling muscle mass in mice by targeting TGF-ß signaling pathways. PLoS ONE 2(8):e789. doi:10.1371/journal.pone.0000789 [PMID: 17726519]

Se-Jin Lee (2008) Genetic analysis of the role of proteolysis in the activation of latent myostatin. PLoS ONE 3(8):e1628. doi:10.1371/journal.pone.0001628 [PMID: 18286185]

Alexandra C. McPherron, Thanh V. Huynh, and Se-Jin Lee (2009) Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev. Biol. 9:24. doi:10.1186/1471-213X-9-24. [PMID: 19298661]

Yuichi Oshima, Noriyuki Ouchi, Masayuki Shimano, David R. Pimentel, Kyriakos N. Papanicolaou, Kalyani D. Panse, Kunihiro Tsuchida, Enrique Lara-Pezzi, Se-Jin Lee, and Kenneth Walsh (2009) Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation 120:1606-1615. [PMID: 19805648]

Kevin J. Morine, Lawrence T. Bish, Joshua T. Selsby, Jeffrey A. Gazzara, Klara Pendrak, Meg M. Sleeper, Elisabeth R. Barton, Se-Jin Lee, and H. L. Sweeney (2010) Activin IIB receptor blockade attenuates dystrophic pathology in a mouse model of Duchenne muscular dystrophy. Muscle Nerve 42:722-730. [PMID: 20730876]

Se-Jin Lee, Yun-Sil Lee, Teresa A. Zimmers, Arshia Soleimani, Martin M. Matzuk, Kunihiro Tsuchida, Ronald D. Cohn, and Elisabeth R. Barton (2010) Regulation of muscle mass by follistatin and activins. Mol. Endocrinol. 24:1998-2008. [PMID: 20810712]

Young Jae Lee, Alexandra McPherron, Susan Choe, Yasuo Sakai, Roshantha A. Chandraratna, Se-Jin Lee, and S. Paul Oh (2010) Growth differentiation factor 11 signaling controls retinoic acid activity for axial vertebral development. Dev. Biol. 347:195-203. [PMID: 20801112]

Saskia C.A. de Jager, Beatriz Bermúdez, Ilze Bot, Rory R. Koenen, Martine Bot, Annemieke Kavelaars, Vivian de Waard, Cobi J. Heijnen, Francisco J.G. Muriana, Christian Weber, Theo J.C. van Berkel, Johan Kuiper, Se-Jin Lee, Rocio Abia, and Erik A.L. Biessen (2011) Growth differentiation 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J. Exp. Med., in press.

Masayuki Shimano, Noriyuki Ouchi, Kazuto Nakamura, Yuichi Oshima, Akiko Higuchi, David R. Pimentel, Kalyani D. Panse, Enrique Lara-Pezzi, Se-Jin Lee, Flora Sam, and Kenneth Walsh (2011) Cardiac myocyte-specific ablation of follistatin-like 3 attenuates stress-induced myocardial hypertrophy. J. Biol. Chem., in press.

INVITED REVIEWS AND COMMENTARIES:

Alexandra C. McPherron and Se-Jin Lee (1996) The transforming growth factor-ß superfamily. In Growth Factors and Cytokines in Health and Disease, vol. 1B. D. LeRoith and C. Bondy, eds. JAI Press, Inc., Greenwich, CT, pp. 357-393.

Se-Jin Lee and Alexandra C. McPherron (1999) Myostatin and the control of skeletal muscle mass. Curr. Opin. Genet. Dev. 9:604-607. [PMID: 10508689]

Se-Jin Lee (2004) Regulation of muscle mass by myostatin. Ann. Rev. Cell Dev. Biol. 20:61-86. [PMID: 15473835]

Se-Jin Lee (2007) Sprinting without myostatin: a genetic determinant of athletic prowess. Trends Genet. 23:475-477. [PMID: 17884234]

Se-Jin Lee (2010) Speed and endurance: you can have it all. J. Appl. Physiol. 109:621-622. [PMID: 20538843]

Se-Jin Lee (2010) Extracellular regulation of myostatin: a molecular rheostat for muscle mass. Immun., Endoc. & Metab. Agents in Med. Chem., 10:183-194.

Se-Jin Lee and David J. Glass (2011) Treating cancer cachexia to treat cancer. Skeletal Muscle, 1:2.

PATENTS:

Se-Jin Lee and Thanh Huynh, Growth Differentiation Factor-6, U.S. Patent 5,770,444, issued June 23, 1998.

Se-Jin Lee and Thanh Huynh, Growth Differentiation Factor-5, U.S. Patent 5,801,014, issued September 1, 1998.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-3, U.S. Patent 5,808,007, issued September 15, 1998.

Se-Jin Lee, Growth Differentiation Factor-9, U.S. Patent 5,821,056, issued October 13, 1998.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-8 (GDF-8) and Polynucleotides Encoding Same, U.S. Patent 5,827,733, issued October 27, 1998.

Se-Jin Lee and Aurora F. Esquela, Polynucleotide Encoding Growth Differentiation Factor-12, U.S. Patent 5,831,054, issued November 3, 1998.

Se-Jin Lee and Alexandra C. McPherron, Methods of Detecting Growth Differentiation Factor-11, U.S. Patent 5,914,234, issued June 22, 1999.

Se-Jin Lee and Aurora F. Esquela, Antibodies to Growth Differentiation Factor-12, U.S. Patent 5,929,213, issued July 27, 1999.

Se-Jin Lee and Thanh Huynh, Polynucleotide Encoding Growth Differentiation Factor-7 and Protein Encoded Thereby, U.S. Patent 5,986,058, issued November 16, 1999.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-8 Transgenic Mice, U.S. Patent 5,994,618, issued November 30, 1999.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-11 Transgenic Mice, U.S. Patent 6,008,434, issued December 28, 1999. Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor 3, U.S. Patent 6,025,475, issued February 15, 2000.

Se-Jin Lee, Use of Growth Differentiation Factor-9 (GDF-9) to Inhibit Oocyte Maturation, U.S. Patent 6,030,617, issued February 29, 2000.

Se-Jin Lee and Thanh Huynh, Growth Differentiation Factor-6, U.S. Patent 6,090,563, issued July 18, 2000.

Se-Jin Lee and Alexandra C. McPherron, Antibodies Specific for Growth Differentiation Factor-8 and Methods of Using Same, U.S. Patent 6,096,506, issued August 1, 2000.

Se-Jin Lee and Aurora F. Esquela, Method for Detection of Growth Differentiation Factor-12 Polypeptide, U.S. Patent 6,130,050, issued October 10, 2000.

Se-Jin Lee, Growth Differentiation Factor-9 Antibodies and Methods, U.S. Patent 6,191,261 B1, issued February 20, 2001.

Se-Jin Lee and Noreen Cunningham, Growth Differentiation Factor-10, U.S. Patent 6,204,047 B1, issued March 20, 2001.

Se-Jin Lee and Thanh Huynh, Antibodies that Bind Growth Differentiation Factor-5, U.S. Patent 6,245,896,issued June 12, 2001.

Se-Jin Lee, Growth Differentiation Factor-9, U.S. Patent 6,365,402 B1, issued April 2, 2002.

Se-Jin Lee and Alexandra C. McPherron, Methods of Detecting Growth Differentiation Factor-3, U.S. Patent 6,391,565 B2, issued May 21, 2002.

Se-Jin Lee, Thanh Huynh, Suzanne Sebald, Christopher Rankin, and Edward Hsiao, Growth Differentiation Factor-15, U.S. Patent 6,420,543 B1, issued July 16, 2002.

Se-Jin Lee, Thanh Huynh, and Suzanne Sebald, Growth Differentiation Factor, Lefty-1, U.S. Patent 6,428,966 B1, issued August 6, 2002.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-8 Nucleic Acid and Polypeptides From Aquatic Species and Non-human Transgenic Aquatic Species, U.S. Patent 6,465,239 B1, issued October 15, 2002.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-8, U.S. Patent 6,468,535 B1, issued October 22, 2002.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-8 Family Nucleic Acid Sequences, U.S. Patent 6,500,664 B1, issued December 31, 2002.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-11, U.S. Patent 6,517,835 B2, issued February 11, 2003.

Se-Jin Lee and Christopher Rankin, Methods of Detecting Growth Differentiation Factor-14, U.S. Patent 6,524,802 B1, issued February 25, 2003. Se-Jin Lee and Alexandra C. McPherron, Methods of Detecting Growth Differentiation Factor-8, U.S. Patent 6,607,884, issued August 19, 2003.

Se-Jin Lee, Thanh Huynh, and Suzanne Sebald, Growth Differentiation Factor, Lefty-2, U.S. Patent 6,635,480 B1, issued October 21, 2003.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor Receptors, Agonists and Antagonists Thereof, and Methods of Using Same, U.S. Patent 6,656,475 B1, issued December 2, 2003.

Se-Jin Lee and Alexandra C. McPherron, Methods for Detection of Mutations in Myostatin Variants, U.S. Patent 6,673,534 B1, issued January 6, 2004.

Se-Jin Lee and Thanh Huynh, Antibodies Specific for Growth Differentiation Factor-7, U.S. Patent 6,680,372 B1, issued January 20, 2004.

Se-Jin Lee and Alexandra C. McPherron, Methods to Identify Growth Differentiation Factor (GDF) Binding Proteins, U.S. Patent 6,696,260 B1, issued February 24, 2004.

Se-Jin Lee and Thanh Huynh, Growth Differentiation Factor-6, U.S. Patent 6,713,302 B1, issued March 30, 2004.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-8, U.S. Patent 6,858,208 B2, issued February 22, 2005.

Se-Jin Lee and Alexandra C. McPherron, Transgenic Non-Human Animals Expressing a Truncated Activin Type II Receptor, U.S. Patent 6,891,082 B2, issued May 10, 2005.

Se-Jin Lee and Thanh Huynh, Method of Detecting Growth Differentiation Factor-7 (GDF-7) using GDF-7 Antibodies, U.S. Patent 7,074,574 B2, issued July 11, 2006.

Se-Jin Lee, Thanh Huynh, and Suzanne Sebald, Growth Differentiation Factor-16, U.S. Patent 7,098,323 B1, issued August 29, 2006.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-8, U.S. Patent 7,179.884 B2, issued February 20, 2007.

Se-Jin Lee and Thanh Huynh, Growth Differentiation Factor-5, U.S. Patent 7,198.790, issued April 3, 2007.

Se-Jin Lee, Thanh Huynh, and Suzanne Sebald, Growth Differentiation Factor, Lefty-2, U.S. Patent 7,270,963, issued September 18, 2007.

Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-8 Nucleic Acid and Polypeptide From Aquatic Species, and Transgenic Aquatic Species, U.S. Patent 7,332,575, issued February 19, 2008.

Se-Jin Lee and Alexandra C. McPherron, Methods for Detection of Mutations in Myostatin Variants, U.S. Patent 7,381,528, issued June 3, 2008. Se-Jin Lee and Alexandra C. McPherron, Growth Differentiation Factor-11, U.S. Patent 7,384,753, issued June 10, 2008.

Se-Jin Lee and Alexandra C. McPherron, Polynucleotides Encoding Promyostatin Polypeptides, U.S. Patent 7,393,682, issued July 1, 2008.

Se-Jin Lee and Alexandra C. McPherron, Polypeptides Encoding Growth Differentiation Factor-8, U.S. Patent 7,399,848, issued July 15, 2008.

Se-Jin Lee, Thanh Huynh, and Suzanne Sebald, Growth Differentiation Factor-16, U.S. Patent 7,495,075, issued February 24, 2009.

Se-Jin Lee and Alexandra C. McPherron, Methods of treating musculodegenerative disease with an antibody that binds growth differentiation factor-8, U.S. Patent 7,534,432, issued May 19, 2009.

Se-Jin Lee and Alexandra C. McPherron, Promyostatin peptides and methods of using same, U.S. Patent 7,566,768, issued July 28, 2009.

Se-Jin Lee, Alexandra C. McPherron, Daniel S. Greenspan, William N. Pappano, Neil Wolfman, and Kathy Tomkinson, Metalloprotease activation of myostatin, and methods of modulating myostatin activity, U.S. Patent 7,572,599, issued August 11, 2009.

Se-Jin Lee and Alexandra C. McPherron, Chicken growth differentiation factor-8, U.S. Patent 7,732,571, issued June 8, 2010. INVITED LECTURES:

Scientific Conferences and Symposia:

Gordon Research Conference: Lysosomes (1988) Gordon Research Conference: Animal Cells and Viruses (1990) 36th Annual Southeast Regional Developmental Biology Conference (1994) 1st International Conference on Bone Morphogenetic Proteins (1994) 15th Annual Congress of the Korean Society of Medical Genetics—plenary speaker (1995) 2nd International Conference on Fibrodysplasia Ossificans Progressiva (1995) 8th Annual TGF-ß Symposium (Japan)—plenary speaker (1997) Gordon Research Conference: Myogenesis (1998) Gordon Research Conference: Myogenesis (2001) FASEB Summer Research Conference: The TGF-ß Superfamily—Signaling and Development (2001) Keystone Symposium: Molecular Control of Adipogenesis and Obesity/Diabetes Mellitus— Molecular Mechanisms, Genetics, and New Therapies (2002) American Physiological Society: Myostatin—symposium chair (2002) Poultry Science Association: Genetic Technology Applied to Poultry Production (2002) American Association for Cancer Research: The TGF-ß Superfamily—Roles in the Pathogenesis of Cancer and Other Diseases (2003) FASEB Summer Research Conference: The TGF-ß Superfamily—Signaling and Development (2003) Society for Developmental Biology, 62nd Annual Meeting—plenary speaker (2003) Developmental Biology Day, University of Alabama at Birmingham (2004) Life Sciences Research Foundation, guest speaker (2005) Spring Symposium of the Korean Society of Endocrinology—plenary speaker (2006) Endocrine Society: Normal and Oncogenic Roles of Activin, Inhibin, and Other TGF-ß Related Ligands (2007) Poultry Performance Workshop (2007) Partnership for Biotechnology Research (Huntsville, Alabama), 9th Annual BioRetreat—keynote speaker (2007) Banbury Center Conference: Molecular Mechanisms Modulating Skeletal Muscle Mass and Function (2008) 2nd Annual Dysferlin Conference (2008) Institute of Myology workshop: Current Advances in the Development of Therapies for Neuromuscular Disorders Based on Myostatin Signaling (2008) Washington University School of Medicine, Department of Pediatrics Retreat—keynote speaker (2009) 3rd Annual Dysferlin Conference (2009) Therapeutic Targets in the Congenital Muscular Dystrophies (2009) The Nature Colloquia on Biomedicine: Colloquium on Frailty—organizer (2010) Parent Project Muscular Dystrophy (2010)

Universities/Research Institutes:

Carnegie Institution of Washington (1988) Massachusetts Institute of Technology (1988) Harvard Medical School (1990) Fox Chase Cancer Center (1990) Harvard University (1990) Johns Hopkins University School of Medicine (1990) SUNY Stony Brook (1991) Stanford Medical School (1991) Massachusetts Institute of Technology (1991) University of Texas Southwestern Medical Center (1991) Columbia College of Physicians and Surgeons (1991) National Institutes of Health (1991) Vanderbilt Medical School (1991) Jackson Lab (1991) National Institutes of Health (1992) Carnegie Institution of Washington (1993) Tokyo Medical and Dental University (1997) University of Virginia Medical School (1998) University of Cincinnati Medical School (1998) Harvard Medical School, Massachusetts General Hospital (1998) Roslin Institute (1998) Carnegie Institution of Washington (1998) University of Texas Southwestern Medical Center (1998) University of Maryland Medical School (1999) Center for Advanced Biotechnology and Medicine (2001) University of Michigan School of Medicine (2002) Mount Sinai School of Medicine (2003) Marshall Space Flight Center (2003) University of Pennsylvania (2003) Boston Obesity Nutrition Research Center (2004) University of Florida (2004) SUNY Stony Brook (2004) Joslin Diabetes Center (2005) New York University Medical Center (2005) Karolinska Institute (2006) University of Wyoming (2007) Boston University School of Medicine (2007) University of Miami School of Medicine (2008) Boston Biomedical Research Institute (2008) University of Maryland School of Medicine (2010) Sanford-Burnham Medical Research Institute (2010) University of Pennsylvania (2011)

Companies:

Genentech, Inc. (1990) Genentech, Inc. (1991) Creative Biomolecules, Inc. (1991) Cambridge Neuroscience, Inc. (1991) Creative Biomolecules, Inc. (1993) Amgen, Inc. (1993) ARES Advanced Technologies (1993) Genetics Institute, Inc. (1994) Proscript, Inc. (1997) Hoechst Marion Roussel—Japan (1997) Eli Lilly and Company (1998) Pfizer, Inc. (1999) Amgen, Inc. (2002) Novartis Biomedical Research Institute (2005) Merck Research Laboratories (2005) Amgen, Inc. (2005) Pfizer, Inc. (2005) Merck Research Laboratories (2006) Acceleron, Inc. (2007) Merck Research Laboratories (2010) NGM Biopharmaceuticals, Inc. (2010) RESEARCH INTERESTS:

Past accomplishments:

The overall focus of our research program is to understand the molecular and cellular mechanisms underlying tissue growth and tissue regeneration with the long-term goal of developing new strategies for treating human diseases. For virtually my entire career, I have been interested in understanding the roles of extracellular signals in regulating embryonic development and adult tissue homeostasis, and almost all of that effort has focused on the superfamily of secreted proteins related to transforming growth factor-ß (TGF-ß). At the time that I became interested in this group of proteins when I was a Staff Associate at the Carnegie Institution of Washington’s Department of Embryology, thirteen members of the TGF-ß family had been described in mammals. Many of these had been shown to play important regulatory roles during embryogenesis and in adult tissues, and many had shown promise for clinical applications, particularly with respect to tissue repair and tissue regeneration. Working on the assumption that many additional family members were yet to be identified and that these would also have biological activities that could be exploited for applications in regenerative medicine, I initiated a screen for new TGF-ß family members by taking advantage of the sequence homologies among the known family members. From this screen, which we continued after I moved my laboratory to Johns Hopkins University School of Medicine, we identified a large number of novel TGF-ß family members that we have designated GDFs (growth/differentiation factors). Currently, the TGF-ß family in mammals encompasses over 35 distinct genes, and about one-third of these were discovered by my laboratory either solely or, in some cases, concurrently with other laboratories. Because many of these GDFs turned out to have highly tissue-specific and cell type- specific expression patterns, understanding their precise biological functions has become the focus of intensive study both by my laboratory and by many others.

Using a variety of experimental strategies, including genetic approaches in mice, my laboratory showed that many of these novel molecules play key roles in regulating a variety of developmental processes. For example, we demonstrated that one of these molecules, GDF-1, is essential for proper formation of the left/right axis during embryogenesis. We showed that mice engineered to lack GDF-1 have a spectrum of defects in left/right patterning, including complete visceral situs inversus in about 50% of mutant embryos [Rankin et al. (2000) Nature Genet. 24:262-265]. Moreover, by examining the expression patterns of other regulatory molecules in Gdf1 mutant embryos, we showed that GDF-1 acts earlier than other genes previously known to be involved in patterning this axis and is an attractive candidate for one of the signaling molecules that may initiate the development of left/right asymmetry. We showed that another molecule, GDF-11, plays an important role in patterning a different embryonic axis, namely, the anterior/posterior axis [McPherron et al. (1999) Nature Genet. 22:260- 264]. We showed that mice lacking GDF-11 have dramatic homeotic transformations of the axial skeleton in which individual vertebrae have morphologies typical of more anteriorly located vertebrae. Furthermore, we showed that Gdf11 mutant mice have altered expression patterns of Hox genes, which are known to be expressed in spatially restricted domains along the anterior/posterior axis during embryogenesis and are believed to be essential for specifying positional identity. Our findings suggest that GDF-11 may be one of the key extracellular signals that act to establish the differential patterns of Hox gene expression along the anterior/posterior axis in the developing embryo. And in collaboration with Dr. David Kingsley’s laboratory at Stanford, we showed that another molecule, GDF-5, plays an important role in regulating skeletal patterning [Storm et al. (1994) Nature 368:639-643]. We showed that mutations in the Gdf5 gene are responsible for the skeletal abnormalities seen in brachypodism mice, providing strong genetic support for the hypothesis that the formation of the skeleton results from the combined actions of multiple members of the TGF-ß superfamily, each acting to regulate the formation of distinct skeletal elements. Our findings provided clear rationales for explaining not only how the skeleton can vary considerably even among highly related species but also why so many molecules with seemingly redundant biological activities may be required to assemble the skeleton in any one species.

Without question, the most significant work of my laboratory has been the discovery of myostatin (GDF-8) and its role as a negative regulator of skeletal muscle mass [McPherron et al. (1997) Nature 387:83-90]. We showed that myostatin is expressed almost exclusively in skeletal muscle tissue both during embryogenesis and in adult animals and that mice in which we knocked out the myostatin gene have a dramatic and widespread increase in skeletal muscle mass. We showed that individual muscles of myostatin knockout mice weigh about twice as much as corresponding muscles from normal mice and that the increase in mass results from a combination of muscle fiber hyperplasia and hypertrophy. Based on these and subsequent studies, it is clear that myostatin performs two functions, one to regulate the number of muscle fibers that are formed during development and a second to regulate the growth of individual muscle fibers postnatally. Our discovery of myostatin and its in vivo function uncovered a completely novel mechanism by which skeletal muscle mass is regulated. Prior to this discovery, there had been no evidence for the existence of a negative regulator of muscle growth. Our findings have not only identified such a regulator but have also raised the possibility that myostatin may be responsible directly or indirectly for the regulation of muscle growth by a variety of other stimuli, including hormones and exercise. Moreover, our discovery of myostatin has revived some archaic theories about the regulation of tissue growth in general. Over 30 years ago, it was hypothesized that the size of a given tissue is controlled by the activity of a negative growth regulator (termed a chalone) that is produced specifically by that tissue and that acts to inhibit the growth of that tissue. Despite extensive efforts to obtain experimental support for this hypothesis, however, no molecules having the essential properties of a chalone have ever been isolated. Based largely on work from my laboratory, it is now clear that myostatin is, in fact, a muscle chalone. Our work has shown that negative growth regulation is an important mechanism for limiting skeletal muscle mass and has raised the possibility that negative regulators of this type may exist for other tissues as well. Hence, the mechanism of action of myostatin may prove to be a paradigm for how tissue growth and tissue size may be regulated throughout the body.

In addition to the scientific significance of this work, our discovery of myostatin has launched a widespread effort in both the academic and pharmaceutical community to exploit the biological properties of myostatin for both agricultural and human therapeutic applications. With respect to agricultural applications, our discovery suggested that blocking myostatin activity in livestock species could be an effective strategy for dramatically improving meat yields to help meet the shrinking world food supply. Indeed, we showed that the myostatin gene has been highly conserved through evolution, and, simultaneously with two other research groups, we demonstrated that mutations in the myostatin gene are the cause of the enhanced muscling seen in certain breeds of cattle that have been described as double-muscled by cattle breeders [McPherron and Lee (1997) Proc. Natl. Acad. Sci., USA 94:12457- 12461]. With respect to human therapeutic applications, our discovery raised the possibility that inhibiting myostatin activity may represent a new strategy for increasing muscle growth and regeneration in the context of disease states characterized by muscle degeneration or wasting. This possibility was bolstered by a collaborative study that we carried out with Dr. Markus Schuelke and his colleagues in Germany in which we characterized a myostatin mutation in a child with about twice the normal muscle mass, thereby providing the first clear evidence that myostatin plays a similar role in humans as it does in mice and in cattle [Schuelke et al. (2004) New Engl. J. Med. 350:2682-2688].

Since our original discovery of myostatin, one major focus of our research effort has been to explore the potential beneficial effects of targeting this pathway in the context of diseases affecting skeletal muscle. For example, we have shown using a mouse model of Duchenne muscular dystrophy that loss of myostatin not only can cause increased muscle mass and strength in the setting of muscle degeneration but can also slow the development of fibrosis, suggesting that targeting myostatin activity may enhance muscle growth and muscle regeneration in patients with muscle degenerative diseases [Wagner et al. (2002) Ann. Neurol. 52:832-836]. We also showed that administration of high levels of myostatin protein to mice can induce a dramatic wasting process similar to the cachexia seen in patients with diseases such as cancer and AIDS [Zimmers et al. (2002) Science 296:1486-1488]. These findings raised the possibility that altered regulation of myostatin activity may play a role in the etiology of cachexia, which is a major cause of mortality in patients with cancer and yet is poorly understood at the mechanistic level. Whether or not altered signaling through this pathway underlies or contributes to the cachexia seen in these patients, our findings raise the possibility that targeting myostatin activity may be an effective strategy for counteracting the wasting process. Finally, we have shown that human therapeutic applications may not be limited just to muscle degenerative and wasting diseases. Using genetic and diet-induced models of obesity, we showed that loss of myostatin can suppress fat accumulation and improve glucose metabolism, raising the possibility that inhibition of myostatin activity may be a novel strategy for the prevention or treatment of metabolic diseases, such as obesity and type II diabetes [McPherron and Lee (2002) J. Clin. Invest. 109:595-601].

In order to pursue these types of applications, we have focused most of our recent research effort on understanding the biology of myostatin at the molecular and cellular level, and we have made considerable progress in terms of understanding some of the basic mechanisms underlying myostatin signaling and regulation. Some of our contributions in this regard include:

 the identification of activin type II receptors as the receptors mediating myostatin signaling in vivo [Lee and McPherron (2001) Proc. Natl. Acad. Sci., USA 98:9306-9311; Lee et al. (2005) Proc. Natl. Acad. Sci., USA 102:18117-18122] .  the demonstration that myostatin exists in a latent, inactive complex with its propeptide [Lee and McPherron (2001) Proc. Natl. Acad. Sci., USA 98:9306-9311] and the elucidation of the mechanisms by which myostatin is activated from this latent complex [Wolfman et al. (2003) Proc. Natl. Acad. Sci., USA 100:15842-15846—collaboration with Daniel Greenspan and with scientists at Wyeth; Lee (2008) PLoS ONE 3(8):e1628].

 the identification of naturally-occurring myostatin binding proteins and the demonstration that these can cause increases in muscle mass when overexpressed in mice [Lee and McPherron (2001) Proc. Natl. Acad. Sci., USA 98:9306-9311; Zimmers et al. (2002) Science 296:1486- 1488; Lee (2007) PLoS ONE 2(8):e789].

 the development of engineered myostatin inhibitors capable of increasing muscle growth when administered systemically to adult mice [Wolfman et al. (2003) Proc. Natl. Acad. Sci., USA 100:15842-15846; Lee et al. (2005) Proc. Natl. Acad. Sci., USA 102:18117-18122; both studies were collaborations with scientists at MetaMorphix and/or Wyeth].

 the demonstration that other TGF-ß family members cooperate with myostatin to limit muscle growth [Lee et al. (2005) Proc. Natl. Acad. Sci., USA 102:18117-18122—collaboration with scientists at Wyeth; Lee (2007) PLoS ONE 2(8):e789].

Current studies:

Virtually all of our current work is focused on further elucidating the signaling and regulatory components involved in the control of muscle growth by myostatin and other TGF-ß family members and on understanding the cellular responses to these signaling molecules. Our continued interest in this area of research stems both from our desire to understand these signaling and regulatory mechanisms at the molecular level and from our goal of exploiting this signaling pathway for applications related to regenerative medicine. The major goals of our current research program are:

 To develop a comprehensive understanding of the roles that members of the TGF-ß family play in regulating muscle homeostasis. Although much of our past work has focused on the role of myostatin in regulating muscle growth, it is clear that other members of this family also function to regulate muscle homeostasis. In previous studies, we have demonstrated the existence of other TGF-ß-related ligands with similar activity to myostatin in muscle. For example, we showed that one myostatin antagonist, a soluble form of the activin type IIB receptor, could cause significant increases in muscle growth when administered not only to wild type mice but also to mice completely lacking myostatin. Similarly, in perhaps the most dramatic series of experiments, I showed that by combining the follistatin transgene with a myostatin null mutation, I was able to generate mice with quadrupled muscle mass, which represents yet another doubling compared to mice completely lacking myostatin. These data demonstrate that additional members of the TGF-ß family cooperate with myostatin to suppress muscle growth, and we are currently carrying out a variety of both genetic and pharmacological approaches to identify these ligands as well as the receptors through which they signal. We believe that these studies will be crucial for understanding the full capacity for muscle growth that can be achieved by targeting this general signaling pathway, which has obvious implications for strategies aimed at promoting muscle growth and regeneration for clinical applications.

 To understand how myostatin activity is regulated extracellularly by binding proteins. In previous studies, we have shown that myostatin exists in an inactive, latent state in which the active portion of the molecule remains bound to and inhibited by its propeptide. We believe that elucidating the mechanisms by which myostatin is activated from this latent state may hold the key to understanding how myostatin activity is regulated in vivo. In this regard, we have identified one mechanism by which myostatin is activated from this latent state, namely, by cleavage of the propeptide by members of the BMP-1/tolloid family of metalloproteases, and we are currently using genetic approaches to determine the identity of the precise protease that acts to regulate myostatin activity in vivo. In addition to the propeptide, a number of other proteins have also been identified that are capable of binding myostatin both in vitro and in vivo, and we are using both biochemical and genetic approaches to understand the roles of these binding proteins in regulating myostatin activity. We believe that elucidating these regulatory mechanisms will be crucial not only for fully understanding the role of myostatin in various physiological processes but also for developing the most optimal strategies for exploiting this pathway for therapeutic intervention.

 To identify the cellular targets for myostatin action in vivo. Despite the significant progress that we have made in terms of understanding the consequences of myostatin signaling with respect to muscle growth, the precise cellular targets for myostatin signaling in muscle are still not fully understood. Based on the increased muscle growth that results from inhibition of myostatin activity in adult animals and based on the effects of myostatin protein on muscle cells in culture, it is presumed that the primary targets for myostatin signaling in muscle are satellite cells, which are the resident stem cells in muscle. Whether myostatin acts directly on satellite cells in vivo and whether myostatin may also signal directly to myofibers are not known. Moreover, a critical issue with respect to the biology of myostatin is whether muscle is the sole target for myostatin action. In particular, we have shown that both loss of myostatin and overexpression of myostatin can have profound effects on adipose tissue, and a major unanswered question is whether these effects reflect direct signaling of myostatin on adipocytes or result indirectly from changes in levels of myostatin signaling in muscle. We are currently attempting to address these questions by using genetic methods either to block or to activate these signaling pathways in specific cell types. We believe that these studies will be essential for further investigating the potential benefits of targeting this signaling pathway both with respect to enhancing muscle growth and with respect to preventing or treating metabolic diseases, like obesity and type II diabetes.

 To identify the intracellular components that mediate myostatin signaling and the downstream genes that regulate muscle growth. Although we made considerable progress in terms of elucidating the mechanisms by which myostatin activity is regulated, we know little about the intracellular pathways mediating myostatin signaling and the downstream cellular responses to myostatin signaling. Understanding these downstream pathways will be critical not only for understanding the basic molecular mechanisms by which muscle growth is regulated but also for developing suitable biomarkers for pathway activity. We are at the early stages of identifying some of the gene expression changes that result from manipulating levels of signaling through this pathway in vivo, and we anticipate that this effort will become a major area of focus, particularly as we develop many of the genetic tools that will enable us to manipulate signaling in specific cell types in mice.

Future directions:

Throughout my career, I have been focused on understanding basic molecular and cellular mechanisms underlying the control of cell-cell signaling with the long-term goal of being able to translate our discoveries into applications related to improving human health. In fact, one of the primary reasons that I became interested in the TGF-ß superfamily when I first became an independent investigator was that the known members of the family had biological activities that could potentially be exploited for clinical applications. In this respect, one of the most personally rewarding aspects of our work to date has been the widespread interest that has been generated in the biomedical community, including the pharmaceutical industry, to target the myostatin pathway to treat human diseases. Indeed, one myostatin inhibitor has already been tested in a clinical trial in patients with muscular dystrophy, and several additional inhibitors will likely be tested in the coming years for a variety of indications. Although much of this effort has progressed to a stage that is beyond the scope of my academic laboratory, I believe that we will be able to continue to contribute to this overall effort using some of the approaches outlined above to address some basic unanswered questions regarding the biology of myostatin. I anticipate that some of these projects will reach suitable endpoints in the near future while others will lead us in new directions with respect to understanding the control of muscle growth as well as the control of the overall metabolic state of the animal. Hence, the general role of these signaling molecules in muscle and other metabolic tissues will likely remain a major focus of my laboratory for a number of years to come. At the same time, one of our long-term goals is to use the myostatin regulatory system as a paradigm for investigating the mechanisms by which growth and regeneration of other tissues may be regulated. It seems unlikely that this type of regulatory system for the control of tissue homeostasis would have evolved only for skeletal muscle and not for other tissues in the body. Of particular interest to us is the possibility that members of the TGF-ß superfamily may be used more widely in other tissues to maintain stem cells in a quiescent state in much the same manner that myostatin may function to suppress activation of muscle stem cells. Our current work on myostatin will form the basis for these future studies, as much of our work has focused on engineering mouse lines carrying inactivating or conditional mutations in various components of this general signaling pathway, including ligands, binding proteins, receptors, and intracellular signaling components, as well as on developing biologics capable of targeting subsets of ligands. Although our short term goal is to use these tools to address many of the questions outlined above, our long-term goal is to use these same tools to explore roles for these signaling molecules and signaling system in other tissues, particularly those in which manipulation of tissue growth or repair could have important applications for regenerative medicine.