2013 Lucian Award: David Ginsburg Susan Ince Circ Res. 2013;113:1286-1289 doi: 10.1161/CIRCRESAHA.113.302984 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/113/12/1286
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014
News & Views 2013 Lucian Award David Ginsburg Susan Ince
T
he 35th Louis and Artur Lucian Award for research in circulatory disease has been presented to physician scientist David Ginsburg, MD, of the University of Michigan, for his groundbreaking work on blood coagulation and cellular protein processing in cardiovascular diseases. Since its beginnings with a $2 million bequest to McGill University in 1965, the Lucian Award has recognized the contributions of active investigators or teams whose work has already had a significant impact on the understanding of cardiovascular disease (Table). In her will, Olga Leibovici established the award to honor her brothers, both engineers, who had died prematurely. The $60 000 CAN prize, the largest given in any biomedical field in Canada, was first awarded in 1978. The Lucian Award places no restrictions on the nationality of the recipients. The McGill University community and awardees benefit from collaborations that are established or furthered during the time winners spend at McGill. Recipients are selected by a committee of scientists, approximately half of whom are former awardees, and each year approximately 15 top-notch applications make it to the last round. “It is remarkable how much Ginsburg has transcended, seemingly effortlessly, traditional division and departmental lines in dealing with medicine, vascular biology, and basic molecular biology. His ability to work within a variety of disciplines is what made him the awardee this year,” says Jacques Genest, MD, FRCP(C), Professor, Faculty of Medicine at McGill University, current Chair of the Lucian Selection Committee, and Novartis Chair in Medicine, McGill University.
Using Genetics to Unravel Bleeding Disorders While a postdoctural fellow in the laboratory of Stuart H. Orkin, MD, at Children’s Hospital, Boston, Massachusetts, Ginsburg was inspired by how thoroughly the identification of hemoglobin genes had transformed understanding of the thalassemias. Ginsburg decided to search for the gene for von Willebrand factor (VWF) to better comprehend von Willebrand disease (VWD), a bleeding disorder that turned up regularly in the clinic but varied so widely that it was often confusing and difficult to diagnose. Independently and simultaneously, Orkin’s laboratory and 3 others cloned and characterized the gene in 1985, laying the The opinions expressed in News & Views are not necessarily those of the editors or of the American Heart Association. Correspondence to [email protected] (Circ Res. 2013;113:1286-1289.) © 2013 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.113.302984
David Ginsburg, MD, received his BA in molecular biophysics and biochemistry from Yale University and his MD from Duke University Medical School. Ginsburg completed a residency in pathology at Presbyterian Hospital in San Francisco, California, and an internship and residency in internal medicine at Peter Bent Brigham Hospital in Boston, Massachusetts. During his subspecialty training in hematology at Harvard Medical School and a research fellowship in the laboratory of Stuart H. Orkin, MD, he began to ask questions about the biology and genetics of the human blood-clotting system. As a postdoctoral fellow, Ginsburg cloned the gene for von Willebrand factor. In 1985, Ginsburg joined the faculty of internal medicine and the Howard Hughes Medical Institute at the University of Michigan Medical School in Ann Arbor, Michigan. Currently, he is a professor in the departments of internal medicine, human genetics, pediatrics, and communicable diseases. Ginsburg is the James V. Neel distinguished university professor of internal medicine and human genetics and the Warner-Lambert/Parke Davis professor of medicine. He continues as an investigator at the Howard Hughes Medical Institute and, in 2002, became a charter member of the Life Sciences Institute at the University of Michigan. Dr Ginsburg is board-certified in internal medicine, with subspecialties in medical oncology and hematology. He is also board-certified in medical genetics. Ginsburg maintains a small clinical practice in medical genetics and general internal medicine. “The academic biomedical life is a great one, and I feel privileged to work in all these areas,” said Ginsburg.
groundwork for future work to dissect the molecular genetic basis of VWD.1 After starting his own laboratory at the University of Michigan, Ginsburg identified various mutations in the gene that defined VWD subtypes and helped explain differences in disease severity. In addition, Ginsburg’s laboratory identified modifier genes that can result in many-fold differences in plasma VWF. While his laboratory has consistently explored VWF, the findings have also led Ginsburg into surprising and fruitful new directions, leading to better understanding
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014 1286
Ince 2013 Lucian Award: David Ginsburg 1287 A
B
Figure 1. A, Low-density lipoprotein receptor is upregulated and proprotein convertase subtilisin/kexin type 9 (PCSK9) is reduced in Sec24−/− mice (reprinted from Chen et al3). B, SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. Figures courtesy of David Ginsburg. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
of a catastrophic clotting disorder, the basic mechanisms of protein transfer within cells, and the means by which certain streptococcal infections become invasive.
From Patients to Systems and Back Again As a physician board-certified in hematology, internal medicine, oncology, and genetics, Ginsburg cares for patients with rare and often mysterious diseases. He became intrigued by thrombotic thrombocytopenic purpura (TTP), an important hemolytic disease that can be either genetic or acquired. Suddenly, patients with TTP (often young and previously healthy) experience development of clots in blood vessels throughout the body. Before treatment with plasma exchange was developed, mortality could be 80% within 2 days. Ginsburg cloned the gene involved in a rare inherited form of TTP and found that it had an important relationship to VWF. It turned out the gene coded for a protease, a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 13 (ADAMTS13), which normally trims the large VWF molecule to the appropriate size so it can stick to platelets and the vessel injury site. When ADAMTS13 is lacking, the VWF protein remains overly large and sticky, sometimes resulting in spontaneous clots. Plasma exchange works by replacing the missing protease. “Besides determining the genetics underlying the inherited forms of TTP, he has helped explain the interaction between the genetic predisposition and triggers and toxins that will result in an attack,” says Genest.
The work on TTP also led to an explanation for type 2a VWD. Instead of lacking ADAMTS13, these patients are overly sensitive to the protease, so their VWF gets cut into abnormally small pieces and bleeding can occur. “The human diseases really taught us how this whole system worked and how von Willebrand’s function is controlled and the way it interacts with blood platelets. And of course we learned a lot about the diseases, including how to measure ADAMTS13 and how to make the diagnosis of TTP. Recombinant proteins are now being developed and hopefully will someday be used as treatment for VWD and TTP,” says Ginsburg.
Protein Trafficking Within Cells When chasing a human disease, Ginsburg has found that the biology often leads a scientist in unanticipated directions. While investigating the cause of a mysterious inherited bleeding disorder, combined factor V and factor VIII deficiency, Ginsburg’s laboratory found the problem not in the genes for the factors themselves but in basic cellular transport. For the first time in mammalian cells, they identified a cargo receptor that sits in the endoplasmic reticulum and helps escort proteins from the endoplasmic reticulum to the Golgi apparatus. Factors V and VIII turned out to be supremely sensitive to mutations in 1 of 2 genes needed to form the cargo receptor. If the carrier complex was missing, then levels of the blood-clotting proteins were reduced ≈90%, creating the bleeding disorder.2 That finding furthered Ginsburg’s interest in intracellular protein transfer, a process well-studied in yeast but not in
Thrombosis Plasmin
↑TF
SK Plasminogen
Cytokines TNFα TGFβ
Local infection
Figure 2. Maintenance of fibrin clot: key host defense against microbial pathogens. PAI1 indicates plasminogen activator inhibitor type 1; SK, streptokinase; TF, tissue factor; TGFβ, transforming growth factor β; and TNFα, tumor necrosis factorα. Figure courtesy of David Ginsburg. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014
1288 Circulation Research December 6, 2013 Table. Previous Recipients of the Lucian Award 1978
Nicolae and Maya Simionescu
Bucharest and Yale University
1979
James Bassingthwaighte
University of Washington
1980
Solbert Permutt
Johns Hopkins University
1981
Gilbert Thompson
Hammersmith Hospital
1982
Christian Crone
University of Copenhagen
1983
Norman Staub
University of California
1984
James and Una Ryan
University of Miami
1985
Earl Wood
Mayo Clinic
1986
Dirk Brutsaert
University of Antwerp
1987
Daniel Steinberg
University of California
1988
Aubrey Taylor
University of South Alabama
1989
Francis Chinard
New Jersey Medical School
Ian Phillips
University of Florida
1990
Barbara Meyrick
Vanderbilt University
1991
José Jalife
State University of New York, Syracuse
1992
Judah Folkman
The Children’s Hospital, Boston
1993
Arthur Brown
Baylor College of Medicine
1994
John B. Barlow
University of Witwatersrand, South Africa
1995
Andrew and Avril Somlyo
University of Virginia, Charlottesville
1996
in 1 copy in yeast but in 4 in humans. SEC24 forms part of the coating of coatomer II coated vesicles involved in endoplasmic reticulum-to-Golgi apparatus transportation. To their surprise, when they created mice lacking 1 of the 4 types, SEC24A, the animals developed normally but had a 45% reduction in plasma cholesterol levels because they were unable to transport the secretory protein PCSK9 (proprotein convertase subtilisin/kexin type 9), a critical regulator of the cell surface low-density lipoprotein receptor. Without PCSK9, levels of the low-density lipoprotein receptor increase and blood cholesterol levels decrease3 (Figure 1). Although clinical questions led Ginsburg into basic research, the findings may have pointed the way toward new cardiovascular disease therapy. An understanding of the cell transport defects in combined factor V/VIII deficiency presents a possible target for new anticoagulant drugs. Many companies are already pursuing various ways to interfere with PCSK9 to lower cholesterol, and SEC24A might present an alternative target. “The implications of this basic research on protein transport are huge,” says Genest.
Lucian Award Selection Committee Jacques Genest Jr, MD Chair, McGill University, Canada
Robert Furchgott
State University of New York
Salvador Moncada
University College, London
1997
Russell Ross
University of Washington
1998
Eduardo Marban
Johns Hopkins University
1999
Victor J. Dzau
Harvard Medical School
2000
Robert J. Lefkowitz
Duke University Medical School
José Jalife, MD
2001
Mark C. Fishman
Harvard Medical School
2002
Salim Yusuf
McMaster University
Richard J. Novick, MD
2003
Eric N. Olson
University of Texas Southwestern Medical Center
2004
Roberto Bolli
University of Louisville
2005
Michael A. Gimbrone, Jr
Harvard Medical School
2006
Peter Carmeliet
University of Leuven
2007
Not Awarded
2008
Piero Anversa
Roberto Bolli, MD University of Louisville, Louisville, KY Dirk L. Brutsaert, MD, PhD Universiteit Antwerpen, Belgium University of Michigan, Ann Arbor, MI University of Western Ontario, Canada Marlene Rabinovitch, MD Stanford University, Stanford, CA Jean L. Rouleau, MD Université de Montréal, Canada Avril V. Somlyo, PhD
Harvard Medical School
University of Virginia, Charlottesville, VA Duncan J. Stewart, MD
2009
Peter Libby
Harvard Medical School
2010
Marlene Rabinovitch
Stanford University School of Medicine
2011
Shaun R. Coughlin
University of California, San Francisco
2012
Garret A. FitzGerald
University of Pennsylvania
2013
David Ginsburg
University of Michigan
University of Ottawa, Canada Emeritus Members Yves Clermont, PhD McGill University, Canada Anthony R.C. Dobell, MD McGill University, Canada
mammals. In recent years, Ginsburg has collaborated with Randy W. Schekman, PhD, of the University of California Berkeley, recipient of the 2013 Nobel Prize in Physiology or Medicine. They were curious about SEC24, a protein present
Samuel O. Freedman, MD McGill University, Canada
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014
Ince 2013 Lucian Award: David Ginsburg 1289
Blocking Bacterial Infection “The ‘blessing and curse’ of genetics is you never know exactly where you’ll end up,” says Ginsburg. Some of his recent work has led from clot formation into the field of infectious diseases. When confronted by bacterial infection, the formation and maintenance of a fibrin clot are key host defenses to block the entrance of bacteria into the bloodstream. All pathogenic group A streptococci produce species-specific streptokinase, a plasminogen activator that dissolves blood clots. Ginsburg’s laboratory showed that streptokinase is critical for allowing the microbes to invade surrounding tissues and cause lethal infections in mice4 (Figure 2). “If we find chemicals that can make the bacteria stop producing streptokinase, then the bacteria can be there but not cause so much harm. And if a compound doesn’t work by killing the bacteria it may not select for resistance as much,” explains Ginsburg. After screening more than 300 000 chemicals, Ginsburg and colleagues5 identified a small set that specifically turned off streptokinase in the bacteria, several of which proved effective in protecting group A streptococci–sensitive mice from fatal infection. “It’s difficult to know where this will lead but, from my point of view, anything that can be learned about the triggering of the coagulation cascade and how it is modified is critically important,” says Genest.
Future of Cardiovascular Disease Genetics During his career, Ginsburg has witnessed—and deployed—the rapidly changing tools available for genetic research. “In my very first research paper, in 1975, we worked for 1.5 years to sequence 4 nucleotides of ribosomal RNA in E. coli. Now, in the lab you routinely sequence a few hundred million base pairs in an afternoon,” recalls Ginsburg. Ginsburg notes that there is still an important role for some old-fashioned genetic tools. To identify additional genetic determinants of VWF levels in the population, his laboratory applied genome-wide association anaIysis, finding a previously recognized association with the ABO blood groups locus but
nothing really surprising. However, linkage analysis based on sibling relationships within the cohort revealed an area on chromosome 2 that explained almost 20% of the variance in VWF levels but was undetected in the genome-wide analysis.6 “We think it’s likely there is a gene in that area with many different variations. Individually the variations are very rare, and that’s why not found by genome-wide association analysis, but in aggregate they account for a lot of people and that’s why we could find by linkage,” says Ginsburg. The group is now sequencing the region in many people and has found some potential candidate genes. For the future, Ginsburg is particularly excited about 2 new techniques, next-generation sequencing and gene editing. “The ability to precisely make just one change in the genome has gotten suddenly, spectacularly easier. You can use it in all kinds of model systems and, I suspect, one day in treating disease in humans. It’s still a ways off, but you can see it’s possible. I tell my students I’m a little jealous that they’re starting their careers now,” Ginsburg says. The next deadline to nominate a scientist for the Lucian Award is March 21, 2014. Further information is available on their website at http://www.mcgill.ca/lucianaward/.
References 1. Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GA, Latt SA, Orkin SH. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science. 1985;228:1401–1406. 2. Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, Wheatley MA, Moussalli MJ, Hauri HP, Ciavarella N, Kaufman RJ, Ginsburg D. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell. 1998;93:61–70. 3. Chen X-W, Wang H, Bajaj K, et al. SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. eLife. 2013;2:e00444. 4. Sun H, Ringdahl U, Homeister JW, Fay WP, Engleberg NC, Yang AY, Rozek LS, Wang X, Sjöbring U, Ginsburg D. Plasminogen is a critical host pathogenicity factor for group A streptococcal infection. Science. 2004;305:1283–1286. 5. Sun H, Xu Y, Sitkiewicz I, Ma Y, Wang X, Yestrepsky BD, Huang Y, Lapadatescu MC, Larsen MJ, Larsen SD, Musser JM Ginsburg D. Inhibitor of streptokinase gene expression improves survival after group A streptococcus infection in mice. Proc Natl Acad Sci U S A. 2012;109:3469–3474. 6. Desch KC, Ozel AB, Siemieniak D, et al. Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association. Proc Natl Acad Sci U S A. 2013;110:588–593.
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/113/12/1286
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014
News & Views 2013 Lucian Award David Ginsburg Susan Ince
T
he 35th Louis and Artur Lucian Award for research in circulatory disease has been presented to physician scientist David Ginsburg, MD, of the University of Michigan, for his groundbreaking work on blood coagulation and cellular protein processing in cardiovascular diseases. Since its beginnings with a $2 million bequest to McGill University in 1965, the Lucian Award has recognized the contributions of active investigators or teams whose work has already had a significant impact on the understanding of cardiovascular disease (Table). In her will, Olga Leibovici established the award to honor her brothers, both engineers, who had died prematurely. The $60 000 CAN prize, the largest given in any biomedical field in Canada, was first awarded in 1978. The Lucian Award places no restrictions on the nationality of the recipients. The McGill University community and awardees benefit from collaborations that are established or furthered during the time winners spend at McGill. Recipients are selected by a committee of scientists, approximately half of whom are former awardees, and each year approximately 15 top-notch applications make it to the last round. “It is remarkable how much Ginsburg has transcended, seemingly effortlessly, traditional division and departmental lines in dealing with medicine, vascular biology, and basic molecular biology. His ability to work within a variety of disciplines is what made him the awardee this year,” says Jacques Genest, MD, FRCP(C), Professor, Faculty of Medicine at McGill University, current Chair of the Lucian Selection Committee, and Novartis Chair in Medicine, McGill University.
Using Genetics to Unravel Bleeding Disorders While a postdoctural fellow in the laboratory of Stuart H. Orkin, MD, at Children’s Hospital, Boston, Massachusetts, Ginsburg was inspired by how thoroughly the identification of hemoglobin genes had transformed understanding of the thalassemias. Ginsburg decided to search for the gene for von Willebrand factor (VWF) to better comprehend von Willebrand disease (VWD), a bleeding disorder that turned up regularly in the clinic but varied so widely that it was often confusing and difficult to diagnose. Independently and simultaneously, Orkin’s laboratory and 3 others cloned and characterized the gene in 1985, laying the The opinions expressed in News & Views are not necessarily those of the editors or of the American Heart Association. Correspondence to [email protected] (Circ Res. 2013;113:1286-1289.) © 2013 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.113.302984
David Ginsburg, MD, received his BA in molecular biophysics and biochemistry from Yale University and his MD from Duke University Medical School. Ginsburg completed a residency in pathology at Presbyterian Hospital in San Francisco, California, and an internship and residency in internal medicine at Peter Bent Brigham Hospital in Boston, Massachusetts. During his subspecialty training in hematology at Harvard Medical School and a research fellowship in the laboratory of Stuart H. Orkin, MD, he began to ask questions about the biology and genetics of the human blood-clotting system. As a postdoctoral fellow, Ginsburg cloned the gene for von Willebrand factor. In 1985, Ginsburg joined the faculty of internal medicine and the Howard Hughes Medical Institute at the University of Michigan Medical School in Ann Arbor, Michigan. Currently, he is a professor in the departments of internal medicine, human genetics, pediatrics, and communicable diseases. Ginsburg is the James V. Neel distinguished university professor of internal medicine and human genetics and the Warner-Lambert/Parke Davis professor of medicine. He continues as an investigator at the Howard Hughes Medical Institute and, in 2002, became a charter member of the Life Sciences Institute at the University of Michigan. Dr Ginsburg is board-certified in internal medicine, with subspecialties in medical oncology and hematology. He is also board-certified in medical genetics. Ginsburg maintains a small clinical practice in medical genetics and general internal medicine. “The academic biomedical life is a great one, and I feel privileged to work in all these areas,” said Ginsburg.
groundwork for future work to dissect the molecular genetic basis of VWD.1 After starting his own laboratory at the University of Michigan, Ginsburg identified various mutations in the gene that defined VWD subtypes and helped explain differences in disease severity. In addition, Ginsburg’s laboratory identified modifier genes that can result in many-fold differences in plasma VWF. While his laboratory has consistently explored VWF, the findings have also led Ginsburg into surprising and fruitful new directions, leading to better understanding
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014 1286
Ince 2013 Lucian Award: David Ginsburg 1287 A
B
Figure 1. A, Low-density lipoprotein receptor is upregulated and proprotein convertase subtilisin/kexin type 9 (PCSK9) is reduced in Sec24−/− mice (reprinted from Chen et al3). B, SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. Figures courtesy of David Ginsburg. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
of a catastrophic clotting disorder, the basic mechanisms of protein transfer within cells, and the means by which certain streptococcal infections become invasive.
From Patients to Systems and Back Again As a physician board-certified in hematology, internal medicine, oncology, and genetics, Ginsburg cares for patients with rare and often mysterious diseases. He became intrigued by thrombotic thrombocytopenic purpura (TTP), an important hemolytic disease that can be either genetic or acquired. Suddenly, patients with TTP (often young and previously healthy) experience development of clots in blood vessels throughout the body. Before treatment with plasma exchange was developed, mortality could be 80% within 2 days. Ginsburg cloned the gene involved in a rare inherited form of TTP and found that it had an important relationship to VWF. It turned out the gene coded for a protease, a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 13 (ADAMTS13), which normally trims the large VWF molecule to the appropriate size so it can stick to platelets and the vessel injury site. When ADAMTS13 is lacking, the VWF protein remains overly large and sticky, sometimes resulting in spontaneous clots. Plasma exchange works by replacing the missing protease. “Besides determining the genetics underlying the inherited forms of TTP, he has helped explain the interaction between the genetic predisposition and triggers and toxins that will result in an attack,” says Genest.
The work on TTP also led to an explanation for type 2a VWD. Instead of lacking ADAMTS13, these patients are overly sensitive to the protease, so their VWF gets cut into abnormally small pieces and bleeding can occur. “The human diseases really taught us how this whole system worked and how von Willebrand’s function is controlled and the way it interacts with blood platelets. And of course we learned a lot about the diseases, including how to measure ADAMTS13 and how to make the diagnosis of TTP. Recombinant proteins are now being developed and hopefully will someday be used as treatment for VWD and TTP,” says Ginsburg.
Protein Trafficking Within Cells When chasing a human disease, Ginsburg has found that the biology often leads a scientist in unanticipated directions. While investigating the cause of a mysterious inherited bleeding disorder, combined factor V and factor VIII deficiency, Ginsburg’s laboratory found the problem not in the genes for the factors themselves but in basic cellular transport. For the first time in mammalian cells, they identified a cargo receptor that sits in the endoplasmic reticulum and helps escort proteins from the endoplasmic reticulum to the Golgi apparatus. Factors V and VIII turned out to be supremely sensitive to mutations in 1 of 2 genes needed to form the cargo receptor. If the carrier complex was missing, then levels of the blood-clotting proteins were reduced ≈90%, creating the bleeding disorder.2 That finding furthered Ginsburg’s interest in intracellular protein transfer, a process well-studied in yeast but not in
Thrombosis Plasmin
↑TF
SK Plasminogen
Cytokines TNFα TGFβ
Local infection
Figure 2. Maintenance of fibrin clot: key host defense against microbial pathogens. PAI1 indicates plasminogen activator inhibitor type 1; SK, streptokinase; TF, tissue factor; TGFβ, transforming growth factor β; and TNFα, tumor necrosis factorα. Figure courtesy of David Ginsburg. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014
1288 Circulation Research December 6, 2013 Table. Previous Recipients of the Lucian Award 1978
Nicolae and Maya Simionescu
Bucharest and Yale University
1979
James Bassingthwaighte
University of Washington
1980
Solbert Permutt
Johns Hopkins University
1981
Gilbert Thompson
Hammersmith Hospital
1982
Christian Crone
University of Copenhagen
1983
Norman Staub
University of California
1984
James and Una Ryan
University of Miami
1985
Earl Wood
Mayo Clinic
1986
Dirk Brutsaert
University of Antwerp
1987
Daniel Steinberg
University of California
1988
Aubrey Taylor
University of South Alabama
1989
Francis Chinard
New Jersey Medical School
Ian Phillips
University of Florida
1990
Barbara Meyrick
Vanderbilt University
1991
José Jalife
State University of New York, Syracuse
1992
Judah Folkman
The Children’s Hospital, Boston
1993
Arthur Brown
Baylor College of Medicine
1994
John B. Barlow
University of Witwatersrand, South Africa
1995
Andrew and Avril Somlyo
University of Virginia, Charlottesville
1996
in 1 copy in yeast but in 4 in humans. SEC24 forms part of the coating of coatomer II coated vesicles involved in endoplasmic reticulum-to-Golgi apparatus transportation. To their surprise, when they created mice lacking 1 of the 4 types, SEC24A, the animals developed normally but had a 45% reduction in plasma cholesterol levels because they were unable to transport the secretory protein PCSK9 (proprotein convertase subtilisin/kexin type 9), a critical regulator of the cell surface low-density lipoprotein receptor. Without PCSK9, levels of the low-density lipoprotein receptor increase and blood cholesterol levels decrease3 (Figure 1). Although clinical questions led Ginsburg into basic research, the findings may have pointed the way toward new cardiovascular disease therapy. An understanding of the cell transport defects in combined factor V/VIII deficiency presents a possible target for new anticoagulant drugs. Many companies are already pursuing various ways to interfere with PCSK9 to lower cholesterol, and SEC24A might present an alternative target. “The implications of this basic research on protein transport are huge,” says Genest.
Lucian Award Selection Committee Jacques Genest Jr, MD Chair, McGill University, Canada
Robert Furchgott
State University of New York
Salvador Moncada
University College, London
1997
Russell Ross
University of Washington
1998
Eduardo Marban
Johns Hopkins University
1999
Victor J. Dzau
Harvard Medical School
2000
Robert J. Lefkowitz
Duke University Medical School
José Jalife, MD
2001
Mark C. Fishman
Harvard Medical School
2002
Salim Yusuf
McMaster University
Richard J. Novick, MD
2003
Eric N. Olson
University of Texas Southwestern Medical Center
2004
Roberto Bolli
University of Louisville
2005
Michael A. Gimbrone, Jr
Harvard Medical School
2006
Peter Carmeliet
University of Leuven
2007
Not Awarded
2008
Piero Anversa
Roberto Bolli, MD University of Louisville, Louisville, KY Dirk L. Brutsaert, MD, PhD Universiteit Antwerpen, Belgium University of Michigan, Ann Arbor, MI University of Western Ontario, Canada Marlene Rabinovitch, MD Stanford University, Stanford, CA Jean L. Rouleau, MD Université de Montréal, Canada Avril V. Somlyo, PhD
Harvard Medical School
University of Virginia, Charlottesville, VA Duncan J. Stewart, MD
2009
Peter Libby
Harvard Medical School
2010
Marlene Rabinovitch
Stanford University School of Medicine
2011
Shaun R. Coughlin
University of California, San Francisco
2012
Garret A. FitzGerald
University of Pennsylvania
2013
David Ginsburg
University of Michigan
University of Ottawa, Canada Emeritus Members Yves Clermont, PhD McGill University, Canada Anthony R.C. Dobell, MD McGill University, Canada
mammals. In recent years, Ginsburg has collaborated with Randy W. Schekman, PhD, of the University of California Berkeley, recipient of the 2013 Nobel Prize in Physiology or Medicine. They were curious about SEC24, a protein present
Samuel O. Freedman, MD McGill University, Canada
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014
Ince 2013 Lucian Award: David Ginsburg 1289
Blocking Bacterial Infection “The ‘blessing and curse’ of genetics is you never know exactly where you’ll end up,” says Ginsburg. Some of his recent work has led from clot formation into the field of infectious diseases. When confronted by bacterial infection, the formation and maintenance of a fibrin clot are key host defenses to block the entrance of bacteria into the bloodstream. All pathogenic group A streptococci produce species-specific streptokinase, a plasminogen activator that dissolves blood clots. Ginsburg’s laboratory showed that streptokinase is critical for allowing the microbes to invade surrounding tissues and cause lethal infections in mice4 (Figure 2). “If we find chemicals that can make the bacteria stop producing streptokinase, then the bacteria can be there but not cause so much harm. And if a compound doesn’t work by killing the bacteria it may not select for resistance as much,” explains Ginsburg. After screening more than 300 000 chemicals, Ginsburg and colleagues5 identified a small set that specifically turned off streptokinase in the bacteria, several of which proved effective in protecting group A streptococci–sensitive mice from fatal infection. “It’s difficult to know where this will lead but, from my point of view, anything that can be learned about the triggering of the coagulation cascade and how it is modified is critically important,” says Genest.
Future of Cardiovascular Disease Genetics During his career, Ginsburg has witnessed—and deployed—the rapidly changing tools available for genetic research. “In my very first research paper, in 1975, we worked for 1.5 years to sequence 4 nucleotides of ribosomal RNA in E. coli. Now, in the lab you routinely sequence a few hundred million base pairs in an afternoon,” recalls Ginsburg. Ginsburg notes that there is still an important role for some old-fashioned genetic tools. To identify additional genetic determinants of VWF levels in the population, his laboratory applied genome-wide association anaIysis, finding a previously recognized association with the ABO blood groups locus but
nothing really surprising. However, linkage analysis based on sibling relationships within the cohort revealed an area on chromosome 2 that explained almost 20% of the variance in VWF levels but was undetected in the genome-wide analysis.6 “We think it’s likely there is a gene in that area with many different variations. Individually the variations are very rare, and that’s why not found by genome-wide association analysis, but in aggregate they account for a lot of people and that’s why we could find by linkage,” says Ginsburg. The group is now sequencing the region in many people and has found some potential candidate genes. For the future, Ginsburg is particularly excited about 2 new techniques, next-generation sequencing and gene editing. “The ability to precisely make just one change in the genome has gotten suddenly, spectacularly easier. You can use it in all kinds of model systems and, I suspect, one day in treating disease in humans. It’s still a ways off, but you can see it’s possible. I tell my students I’m a little jealous that they’re starting their careers now,” Ginsburg says. The next deadline to nominate a scientist for the Lucian Award is March 21, 2014. Further information is available on their website at http://www.mcgill.ca/lucianaward/.
References 1. Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GA, Latt SA, Orkin SH. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science. 1985;228:1401–1406. 2. Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, Wheatley MA, Moussalli MJ, Hauri HP, Ciavarella N, Kaufman RJ, Ginsburg D. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell. 1998;93:61–70. 3. Chen X-W, Wang H, Bajaj K, et al. SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. eLife. 2013;2:e00444. 4. Sun H, Ringdahl U, Homeister JW, Fay WP, Engleberg NC, Yang AY, Rozek LS, Wang X, Sjöbring U, Ginsburg D. Plasminogen is a critical host pathogenicity factor for group A streptococcal infection. Science. 2004;305:1283–1286. 5. Sun H, Xu Y, Sitkiewicz I, Ma Y, Wang X, Yestrepsky BD, Huang Y, Lapadatescu MC, Larsen MJ, Larsen SD, Musser JM Ginsburg D. Inhibitor of streptokinase gene expression improves survival after group A streptococcus infection in mice. Proc Natl Acad Sci U S A. 2012;109:3469–3474. 6. Desch KC, Ozel AB, Siemieniak D, et al. Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association. Proc Natl Acad Sci U S A. 2013;110:588–593.
Downloaded from http://circres.ahajournals.org/ by guest on January 2, 2014
