News & Media

March 2009
Director's Corner: George Karpati (1934 - 2009) - a born scientist

Because he was such a big part of how we, and the world, see our institution, George's loss is an important moment in our history. His achievements, and his personal character, were both on an epic scale, and his loss is a major blow to the Institute. With his unique vitality he seemed a primeval and eternal force, and it is shocking and disorienting to suddenly find that he was as ephemeral as any of us.

When I was asked to summarize George's scientific work at the Neuro for the Director's Corner column, I chose the title above because it gives me a chance to point out what will be the greatest loss for those of us in the Neuromuscular Group that George founded, who worked with him every day. We will of course miss him as a deep well of knowledge based on the life's work of a sharp mind. But an even bigger loss to us than his scientific knowledge will be his attitude towards science. George was a born scientist. Nothing gave him greater pleasure than learning a new and unexpected fact or concept. He had a child-like joy in taking hold of the new fact or idea and twisting it this way and that, looking at it from all angles, and drawing out all manner of conclusions and speculations, including the wildest speculations. This was done at high speed with a big smile and a loud voice and usually in the form of rapid fire questions to the person he was with. This explosive and creative imagination is not something you can learn - you have to be born with it, and George was. It was as much a part of him as breathing, and it continued absolutely unabated throughout all the years we knew him. It both supported his scientific achievements, by providing an effective mechanism for assimilating new ideas, and was in itself a motivation to learn and discover new things, because he enjoyed it so much. To be party to this joyful attitude was a daily source of inspiration and stimulation to the rest of us in the Neuromuscular Group, and to many others at the Neuro, and that leaves a gap that will not be filled. In the group there is an excellent esprit, and we have the greatest respect for each other's capabilities, but we all know that from now on, it won't be quite as much fun as it was.

George's focus on neuromuscular disease research emerged in conjunction with his postdoctoral research training with W. King Engel at the National Institutes of Health in the USA in the mid-60's. Right from the beginning, George had a particular interest in cell biology and in molecular explanations for disease. This led him to develop himself into one of the world's top myopathologists and a uniquely effective neuromuscular clinician. He joined the Neuro in 1967 and his early work here, both in diagnosis and in research, was often a collaborative effort with his close MNI colleague, the neuropathologist Stirling Carpenter, with whom he co-authored a classic textbook on myopathology. Two more different people could not be imagined - George ebullient and loquacious, Stirling still and laconic, though with a constant smile - but they were a superb team and great friends. Another important early Neuro collaborator was Sergio Pena, whose Latin temperament meshed so well with George's Hungarian flair that they remained close friends even after Sergio returned to his native Brazil.

When George looked into the microscope he did not see a remote, static world, but a snapshot of a dynamic and immediately relevant system to be simultaneously interpreted down to the level of the molecules and up to the level of the specific patient in one sweeping view. His conviction that real understanding and advance must come from deep knowledge at the cell/molecular level is clearly reflected in the way he built up the Neuromuscular Research Group at the Neuro over the years. He was the organizing mind, and the scientific nucleus, for the attraction of a strong group with diverse interests in muscle and nerve where the common language is that of cell/molecular biology and genetics. Cell biologist Heather Durham, with a major interest in motor neurons, and biochemist Paul Holland, with a particular interest in muscle, were later joined by the Neuro's first molecular biologist (Ken Hastings) and by Eric Shoubridge whose interest in metabolism soon developed, with George's enthusiastic clinical collaboration, in the direction of molecular genetics of neuromuscular disease, an area further stengthened by the recent recruitment of clinician-scientist Michael Sinnreich. In its ongoing work, this group is a living legacy of George's organizational energy and sound scientific instincts.

George's early work at the Neuro included clinical studies on a variety of conditions including commonly observed neuromuscular conditions like polymyositis. He also fully appreciated the insight to be generated from study of animal models and he published important experimental studies on muscle and its control by nerve, including the development and maintenance of fiber-type-specific properties. He also showed in his early work a special appreciation for the importance of genetic factors in disease.

Although George always maintained wide-ranging professional interests, key mid-career events in the 1980's brought a major change and an increased focus on a specific problem. The emergence of molecular biology and molecular genetics led to several breakthroughs at that time including the identification of the gene responsible for Duchenne/Becker muscular dystrophy (DMD)- the most infamous neuromuscular disease. This gene was identified and cloned in 1985 in the Kunkel lab at Harvard and the Worton lab at Toronto. George's expertise in microscopic analysis was critical in a collaboration with the Worton group that identified the intracellular location of the protein encoded by the gene - called "dystrophin" after the disease. The dystrophin protein localization established by George was at the surface plasma membrane (sarcolemma) of the muscle cell and not, as an earlier report had indicated, the internal "triad" membrane system. From the abstract of his 1988 Nature paper with the Worton group.... "We conclude that the product of the DMD gene is associated with the sarcolemma rather than with the triads and speculate that it strengthens the sarcolemma by anchoring elements of the internal cytoskeleton to the surface membrane." This remains the leading hypothesis regarding the molecular pathology of the disease.

Though it is very difficult to point to one element as paramount in the rich tapestry of George's scientific work, which is reported in approximately 250 published papers, the localization of dystrophin could perhaps be considered his most important single contribution. However this was not what George had in mind at that time; for him this was only the prelude to something much bigger. With the discovery of the DMD gene it appeared to George that here was a cure for this terrible disease just waiting to be applied. Thus began a major chapter in his research career, on gene therapy, i.e. the goal of supplying to the muscle cells of affected boys normal copies of the dystrophin gene, which would functionally replace their own defective version. George energetically explored two approaches, initially a cell-based approach - myoblast transplantation - and subsequently gene therapy with viral vectors.

George worked on the development of "mini-dystrophin genes" (the intact dystrophin gene is unworkably large - in fact it is the largest in the human genome) and various viral vectors, often working closely with Paul Holland, Basil Petrof of the Meakins-Christie Labs at McGill, and with Josephine Nalbantoglu, who became an increasingly important collaborator throughout his later career.

It is very sad that George did not live to see his dream of gene therapy for muscular dystrophy become reality. Although straightforward in theory, and despite promising pre-clinical results in animal models and a handful of successful cases in particular diseases, the actual practice of human gene therapy has turned out to be fraught with major technical difficulties that have impeded the best efforts of the world-wide community of genetics clinicians/researchers. Great progress has been made, by George and by others, in identifying the specific problems that will have to be solved to make gene therapy a widely-applicable procedure. But it is left for a new generation of clinicians and gene therapy researchers, including Renald Gilbert, Hans Lochmuller, Gyula Acsadi, and An-Bang Liu, who trained in George's lab, to make those final steps. To them he leaves a legacy of knowledge and training, and also the challenge that drove his own ceaseless work. As he recently said in remarks aimed at young scientists -"Keep reaching for the stars; they are very, very high up there." That was a philosophy he lived full-tilt all his life, right up to the end.

Please send any comments about the Director's Corner to David Colman

Recent News & Events

Building new scientists
It’s common to find 20-somethings at the Neuro learning to do research but scientists here are introducing younger students to science. With an experience that inspires everyone, David Colman, Angela Genge and Bruce Pike, parents of students at St George’s School of Montreal, have invited some high school students into their labs and opened doors to other labs as well. This fall, Miranda Tradewell, post-doctoral fellow in Heather Durham’s lab, took MNI staff member Helmut Bernhard’s daughter and lab partner under her wing, and helped them learn how to sample and assess bacteria levels on common surfaces throughout their school. Their month of work paid off as these Laurier Senior High School students have been chosen to present their results at the Bell Regional Science Fair in March.

Upcoming events

Don’t be shy….
The Spring Fling, MNI’s annual talent show, will be April 30, and anyone who plans to perform should register by April 17 with Anthony Bruce at local 1901. Musicians, comedians, singers and others are welcome. Display tables will also be available.

Social Night Fundraiser for Brain Tumours
The fifth annual Franco Di Giovanni Foundation Social Night Fundraiser will take place on Saturday, March 28 at Prima Luna Reception Hall (7301 Henri Bourassa Boulevard East). Cocktails start at 5:30 p.m. and dinner at 6:30 p.m. There will be door prizes, an auction of sports memorabilia and other items. All proceeds will go towards brain tumour research at the Montreal Neurological Institute and Hospital. Tickets are $100 each. For tickets and more information contact: Ms. Lina Di Giovanni at (514) 494-6831 or Mr. Mike Talevi at (514) 352-6730.

Congratulations to ...

Andrew Reader who received one of 9 Canada Research Chairs (CRC) awarded at McGill, and one of only 134 awarded nationally. Andrew was awarded salary support through a Tier 2 CRC and funds for equipment in his lab from the Canadian Foundation for Innovation.

Condolences to …

The friends and family of Thérèse Lavoie-Roux (1928-2009), advocate for social justice and women’s rights who died January 31, 2009. Mme Lavoie-Roux was Quebec Minister of Health and Social Services in the Bourassa government and a federal Senator from 1990-2001. She also served on the McGill University Board of Govenors, and on the Advisory Board of the Montreal Neurological Institute from 1992-2002.

Director - David R. Colman, PhD
Senior Management - Mark Angle, MD; Phil Barker, PhD; Rob Dunn, PhD; Tom Gevas, Marilyn Kaplow, Elizabeth Kofron, PhD; Patricia O'Connor, Catherine Rowe, Donatella Tampieri, MD
Neuro News: Elizabeth Kofron, PhD & Sandra McPherson, PhD

Please send any items for the Neuro News to Sandra McPherson or Beth Kofron.