In Context
Profile Steven Greenberg: putting CAA on the map Cambridge, Massachusetts, was still in the icy grip of a severe North American winter when The Lancet Neurology caught up with Steven Greenberg in February, but the easy warmth of the native Philadelphian was more than enough to break the conversational ice. Professor of Neurology at Harvard Medical School and Director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital, Greenberg is an “innovative researcher, who has the cognitive skill set to bring consensus to difficult scientific questions”, says Philip Gorelick, Professor of Translational Science and Molecular Medicine at the Michigan State University College of Human Medicine. And foremost among those questions is the problem of how to get to grips with cerebral amyloid angiopathy (CAA). “It is becoming increasingly clear that cognitive decline in the elderly is often due to a combination of cerebrovascular disease and neurodegeneration”, notes Stephen Salloway, Professor of Neurology and Psychiatry at Brown University in Rhode Island, and Greenberg has “helped pioneer the critical field at the juncture between stroke and Alzheimer’s disease”, he says. Now widely viewed as the leading authority on the causes, diagnosis, and treatment of CAA, Greenberg is at an amused loss to explain how he got there. As an undergraduate he studied biochemistry at Harvard until graduation in 1981, when he made the short trip to New York and Columbia University for his MD and PhD. He’d initially been attracted to neurology by the big philosophical questions surrounding the nature of consciousness that remain resolutely unresolved. “It reminds me of all those episodes of Star Trek, where they smirk about how little people knew in the 20th century”, he laughs. “For all our progress, when it comes to thinking about how what we feel as consciousness arises from the physical processes of the brain, we’re still talking about a ghost in the machine. People will laugh at how little we knew about the brain at the start of the 21st century.” At Columbia’s Center for Neurobiology and Behavior, under the expert guidance of James Schwartz and Eric Kandel, Greenberg worked on one of neurology’s other big questions, probing the mechanisms behind the formation of memories, before going on to complete his internship in the Department of Internal Medicine at Pennsylvania Hospital in his home town of Philadelphia in 1989. A 3-year stint as resident in the Department of Neurology at Massachusetts General Hospital in Boston followed, before he returned to basic research in 1992, as a fellow at the Center for Neurologic Diseases at Boston’s Brigham and Women’s Hospital, under the supervision of Kenneth Kosik and Dennis Selkoe. www.thelancet.com/neurology Vol 13 April 2014
Under Kosik and Selkoe, Greenberg started to work on the underlying mechanisms of Alzheimer’s disease. And although it was intimately linked to his earlier work on memory, the work “forced one to put those bigger questions to one side”, he explains. It was during this time that Greenberg began to realise perhaps his future lay in more patient-centred research. “I’ve no idea if it actually happened like I remember it”, he laughs, “but I was running a gel that was just about to finish, and I got a phone call from a patient. All I wanted to do was get to this gel before it was ruined, but I couldn’t hang up on a patient. It really encapsulated this feeling that I was being pulled in two different directions.” At the same time, patients presenting with unexpected types of symptoms began to show Greenberg that CAA, which had previously been thought rare and only identifiable on autopsy, might be much more common than had previously been supposed, and a potentially important driver of age-related cognitive decline. The more he looked into it, the more Greenberg realised how little was known about it, and how well placed he was to study it in depth, moving to the Neurology Clinical Trials Unit and founding the Hemorrhagic Stroke Research Program at Massachusetts General Hospital in 1994. Greenberg has been Director of the haemorrhagic stroke programme since 2002, and in that time has witnessed an increasing recognition in the international stroke community of the clinical importance of CAA. However, as yet, there is no treatment for CAA and only one ongoing clinical trial (a phase 2 study of a monoclonal antibody). One of the main barriers to trial design is the lack of agreement about how best to measure the effectiveness of any treatment. “Drug companies don’t expect every drug to work, but they do need ways of assessing quickly whether something has potential”, says Greenberg, and we provide investigators with “a buffet of outcome measures to test the effectiveness of new treatments”, he explains. Whether or not he has helped find a cure for CAA by the end of his career, Greenberg hopes he has at least helped put the disease on the map. And as Washington University’s Randy Bateman explains, the army of young stroke and cognitive neurology investigators that Greenberg has trained will carry the flame for CAA for generations to come. “Steve is a wonderful, brilliant neurologist who radiates excitement for the future of neurological treatments in cerebral amyloid angiopathy”, says Bateman. “Much in the same way that Carl Sagan enthralled people about astronomy, Steve inspires others to make a meaningful difference in research and therapeutic applications in neurology.”
See Review page 419
David Holmes 349
Profile Steven Greenberg: putting CAA on the map Cambridge, Massachusetts, was still in the icy grip of a severe North American winter when The Lancet Neurology caught up with Steven Greenberg in February, but the easy warmth of the native Philadelphian was more than enough to break the conversational ice. Professor of Neurology at Harvard Medical School and Director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital, Greenberg is an “innovative researcher, who has the cognitive skill set to bring consensus to difficult scientific questions”, says Philip Gorelick, Professor of Translational Science and Molecular Medicine at the Michigan State University College of Human Medicine. And foremost among those questions is the problem of how to get to grips with cerebral amyloid angiopathy (CAA). “It is becoming increasingly clear that cognitive decline in the elderly is often due to a combination of cerebrovascular disease and neurodegeneration”, notes Stephen Salloway, Professor of Neurology and Psychiatry at Brown University in Rhode Island, and Greenberg has “helped pioneer the critical field at the juncture between stroke and Alzheimer’s disease”, he says. Now widely viewed as the leading authority on the causes, diagnosis, and treatment of CAA, Greenberg is at an amused loss to explain how he got there. As an undergraduate he studied biochemistry at Harvard until graduation in 1981, when he made the short trip to New York and Columbia University for his MD and PhD. He’d initially been attracted to neurology by the big philosophical questions surrounding the nature of consciousness that remain resolutely unresolved. “It reminds me of all those episodes of Star Trek, where they smirk about how little people knew in the 20th century”, he laughs. “For all our progress, when it comes to thinking about how what we feel as consciousness arises from the physical processes of the brain, we’re still talking about a ghost in the machine. People will laugh at how little we knew about the brain at the start of the 21st century.” At Columbia’s Center for Neurobiology and Behavior, under the expert guidance of James Schwartz and Eric Kandel, Greenberg worked on one of neurology’s other big questions, probing the mechanisms behind the formation of memories, before going on to complete his internship in the Department of Internal Medicine at Pennsylvania Hospital in his home town of Philadelphia in 1989. A 3-year stint as resident in the Department of Neurology at Massachusetts General Hospital in Boston followed, before he returned to basic research in 1992, as a fellow at the Center for Neurologic Diseases at Boston’s Brigham and Women’s Hospital, under the supervision of Kenneth Kosik and Dennis Selkoe. www.thelancet.com/neurology Vol 13 April 2014
Under Kosik and Selkoe, Greenberg started to work on the underlying mechanisms of Alzheimer’s disease. And although it was intimately linked to his earlier work on memory, the work “forced one to put those bigger questions to one side”, he explains. It was during this time that Greenberg began to realise perhaps his future lay in more patient-centred research. “I’ve no idea if it actually happened like I remember it”, he laughs, “but I was running a gel that was just about to finish, and I got a phone call from a patient. All I wanted to do was get to this gel before it was ruined, but I couldn’t hang up on a patient. It really encapsulated this feeling that I was being pulled in two different directions.” At the same time, patients presenting with unexpected types of symptoms began to show Greenberg that CAA, which had previously been thought rare and only identifiable on autopsy, might be much more common than had previously been supposed, and a potentially important driver of age-related cognitive decline. The more he looked into it, the more Greenberg realised how little was known about it, and how well placed he was to study it in depth, moving to the Neurology Clinical Trials Unit and founding the Hemorrhagic Stroke Research Program at Massachusetts General Hospital in 1994. Greenberg has been Director of the haemorrhagic stroke programme since 2002, and in that time has witnessed an increasing recognition in the international stroke community of the clinical importance of CAA. However, as yet, there is no treatment for CAA and only one ongoing clinical trial (a phase 2 study of a monoclonal antibody). One of the main barriers to trial design is the lack of agreement about how best to measure the effectiveness of any treatment. “Drug companies don’t expect every drug to work, but they do need ways of assessing quickly whether something has potential”, says Greenberg, and we provide investigators with “a buffet of outcome measures to test the effectiveness of new treatments”, he explains. Whether or not he has helped find a cure for CAA by the end of his career, Greenberg hopes he has at least helped put the disease on the map. And as Washington University’s Randy Bateman explains, the army of young stroke and cognitive neurology investigators that Greenberg has trained will carry the flame for CAA for generations to come. “Steve is a wonderful, brilliant neurologist who radiates excitement for the future of neurological treatments in cerebral amyloid angiopathy”, says Bateman. “Much in the same way that Carl Sagan enthralled people about astronomy, Steve inspires others to make a meaningful difference in research and therapeutic applications in neurology.”
See Review page 419
David Holmes 349
