Niamh McGarry

The need to better understand, treat and even prevent diseases such as Alzheimer’s and Parkinson’s grows increasingly urgent as Canada’s population ages. In this conclusion of her two-part series on the 91�Թ�’s world renowned Tanz Centre for Research in Neurodegenerative Diseases, writer Niamh McGarry looks at how 91�Թ� scientists are leading the way.

Two decades ago, the decision to create a standalone, disease-based Centre focused exclusively on Alzheimer’s disease and other neurodegenerative diseases was both visionary and way ahead of its time, says Tanz Centre researcher and Jeno Diener Chair in Neurodegenerative Disease, Prof. Paul Fraser.

The current team of highly skilled primary investigators includes researchers with different disease emphasis and expertise—from genetics (Peter St George-Hyslop, Ekaterina Rogaeva); biophysics (Paul Fraser); protein interactions (Gerold Schmitt-Ulms); RNA (Janice Robertson); to the generation of cell models and stem cells (Anurag Tandon); model organisms, such as worms (Hiroshi Suzuki) or rodents (Howard Mount [B.Sc. ’82, M.Sc. ’86]); to neuroimaging (Carmela Tartaglia); the study of behaviour (Howard Mount); and neuropathology (Lili-Naz Hazrati).

This breadth of knowledge enables a discovery in one domain to rapidly be passed to researchers with complementary skills and tools for the next stage in the discovery pipeline. This is exactly what happened with the groundbreaking presenilin discoveries.

“We had the expertise in-house to immediately undertake studies of the protein and its function, and to make cellular and transgenic models,” explains St George-Hyslop.

A global trend toward “big science” has increasingly translated into partnerships between the Centre and international research programs, including the Alzheimer’s disease Genetics Consortium, which conducts pioneering, genome-wide association studies on more than 20,000 samples to identify genes that confer an increased risk of developing late-onset Alzheimer’s disease.

A couple of years ago, the Centre received an $8.8 million grant from the Wellcome Trust and the Medical Research Council in the United Kingdom and the Canadian Institutes of Health Research to work with laboratories in Germany and the UK on fundamental questions related to Alzheimer’s disease. St George-Hyslop leads the international consortium.

“It’s a highly productive collaboration and there will be some impressive results coming out of it in the next year or two,” he predicts.

In addition, the Tanz Centre is part of a more recent British government push to rapidly move research from the bench to the clinic. Early discussions are underway with the Centre for Addiction and Mental Health, and Sunnybrook Health Sciences Centre, to replicate the initiative in Toronto.

The Tanz Centre has also forged links with China, securing two of the three new team grants funded jointly by the Canadian Institutes of Health Research and the National Science Foundation of China.

These collaborative initiatives have helped turn the Tanz Centre into a powerhouse for neurodegenerative research, and provided a unique and highly productive training environment for the next generation of scientists. The institute’s H-index rating (a measure of the productivity and impact of the most highly cited work published by a scientist or institute) is 47, according to a publication analysis conducted last year at 91�Թ�.

This places it second worldwide in the number and impact of its scientific publications in the neurodegenerative research field after the McGovern Institute for Brain Research at the Massachusetts Institute for Technology.

The Tanz Centre excels in all measures of success—awards, prizes, patents, peer-reviewed funding grants and name recognition—to such an extent that several other universities have been inspired to launch their own institutes with similar names and foci across North America. In the new millennium alone, Tanz Centre scientists have been awarded more than 50 major international and national scientific awards and prizes, and received roughly $50 million in peer reviewed funding.

Still, neurodegenerative disease research in Canada remains chronically underfunded compared to countries such as Germany and France. In fact, both the existence of the Tanz Centre and its continued success would be unthinkable if it were not for four sources of funding: philanthropy from private individuals including Mark Tanz (BA ’52, Honourary Doctor of Laws ’90), Lionel Schipper (BA ’53, LLB ’56, Honourary Doctor of Laws ’00) and others; the Alzheimer Society of Ontario, which has contributed $11 million over twenty years; the Canadian Institutes of Health Research; and the Ontario Research Fund from the provincial government.

“All played a critical role, and their continued support is vital to keep us going,” says St George-Hyslop.

Mark Tanz and Lionel Schipper are spearheading new fundraising efforts for a state-of-the-art location for the Centre in the Krembil Discovery Tower, currently rising from the ground beside the Toronto Western Hospital. The move, scheduled for 2013, is highly anticipated. The Tanz Centre has been housed from the beginning on the edge of the 91�Թ� campus at College and University, in a historic building from the 1930s that was not designed for molecular science.

The move to the new building, to be equipped with $8 million in leading-edge facilities, is expected to provide much-anticipated access to advanced imaging technology, modern equipment for the characterization of proteins and a major biobank with 80 freezers for storing tissue cultures. With a planned expansion to 14 laboratories, a lecture theatre, and the use of centralized seminar rooms, the Tanz Centre will be in the position to recruit new investigators in areas such as systems biology and stem cell research.

The new premises, and the increased access to technological and biological innovations it will facilitate, will ensure that the Tanz Centre remains at the forefront of international efforts to untangle the secrets of the brain.

“Right now neurodegenerative diseases are lethal disorders. In probably 10 to 15 years, we will view it like we currently view some cancers: there will be good specific medicines for certain types of these disorders,” predicts Prof. St George-Hyslop.

Eventually, he sees the Centre moving toward brain repair.

“Once we have ways to stop the disease, we still need to correct the damage already done. This will require a new phase of research: how to repair the brain damaged by neurodegenerative diseases.”

Building on the discoveries of the past two decades, Tanz Centre researchers and their supporters look forward to forging this next exciting phase of discovery.

Missed the first part of the series on the Tanz Centre? You can read it here.

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The Tanz Centre: 20 years of discovery

sgupta — Tue, 29 May 2012 14:35:23 +0000

The Tanz Centre: 20 years of discovery sgupta Tue, 05/29/2012 - 10:35

Cutline

Scientists at 91�Թ�'s Tanz Centre have shaped the course of neurodegenerative disease research (image by 91�Թ� News)

Niamh McGarry

Author legacy

Niamh McGarry

Topic

The need to better understand, treat and even prevent diseases such as Alzheimer’s and Parkinson’s grows increasingly urgent as Canada’s population ages. In this first instalment of a two-part series on the 91�Թ�’s world renowned Tanz Centre for Research in Neurodegenerative Diseases, writer Niamh McGarry looks at how 91�Թ� scientists are leading the way.

There will be no single “lucky break” that provides an overnight solution to neurodegenerative diseases, predicts Professor Peter St George-Hyslop, director of the 91�Թ�’s Tanz Centre for Research in Neurodegenerative Diseases.

“Despite more than a hundred years looking at Alzheimer’s and Parkinson’s diseases, no one has made that serendipitous discovery that instantaneously provides a cure,” says the distinguished neurologist and molecular geneticist.

Meanwhile, an increasingly elderly population accentuates the burden of these diseases worldwide.

“These disorders are very complicated; they occur in the most complex organ of the body, housed in a place that is very difficult to get at,” St George-Hyslop says.

“By working from an understanding of the underlying mechanisms that are activated by causative factors, you get a much more rational idea of what the appropriate therapeutic targets are, and how you can diagnose disease before you’ve got substantial damage.”

The Tanz Centre was founded in 1990 to tackle these fundamental challenges presented by neurodegenerative diseases. In the last two decades it has strategically recruited scientific investigators with complementary skills, expertise and leading-edge scientific methods to create a highly productive and innovative institute.

“While the institute largely focuses on Alzheimer’s disease (AD), we long ago realized that by also working on other neurodegenerative diseases, we learn useful things relevant to AD, and that goes in both directions,” says St George-Hyslop.

As a result, the Centre also has strong research programs in Parkinson’s disease, amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and prion diseases, sometimes referred to as Creutzfeldt-Jakob disease in humans or “mad cow disease” in cattle.

Research scientists at the Tanz Centre first made international headlines in 1992 when they narrowed in on a region of chromosome 14 that appeared to be responsible for many of the inherited cases of early-onset Alzheimer’s disease. Three years later, they were the first worldwide to identify the actual gene, presenilin 1, on chromosome 14 that causes this form of very aggressive AD. They followed that achievement with the discovery of a related, early-onset, AD-causing gene called presenilin 2, a few months later.

The function of the presenilin gene products is related to the generation of the amyloid-beta peptide, a substance that collects in the brains of Alzheimer’s patients in so-called amyloid plaques and is thought to be a key factor in the initiation of the disease.

The presenilin discoveries were a breakthrough that placed the fledgling Centre on the international research map. Still, the discovery of presenilins was considered by some to be a “flash in the pan,” says Tanz Centre researcher and Jeno Diener Chair in Neurodegenerative Disease, Professor Paul Fraser.

“Then we discovered nicastrin.”

The Centre has shown presenilins work in concert not only with nicastrin but also with a number of other proteins, which together comprise a distinct and previously unknown molecular machine that plays a key role in AD, but which is also essential for life. Multiple possibilities for therapeutic intervention emerged from these findings, some of which are being tested in ongoing clinical trials.

Genetics offers some of the most powerful tools that have been used within the Centre to enable groundbreaking discoveries in Alzheimer’s disease, Parkinson’s disease and frontal temporal dementia. Recently, genetic research at the Centre contributed to the discovery of a gene (C90RF72) responsible for more than 30 percent of ALS/frontal temporal dementia cases.

"A particular strength of genetics is that it can provide a firm causative link between a gene and a disease,” says Tanz Centre researcher and Department of Medicine Professor Ekaterina Rogaeva. “Once established, and if the linkage is strong, then genetics may also enable disease to be diagnosed pre-symptomatically.

"In the future, genetics could provide the key to selecting not only the most suitable cohort of individuals for a given clinical trial but may be used also to target individuals at risk of developing Alzheimer’s disease for early intervention.”

But it is not all about genetics at the Tanz Centre. In fact, the Centre’s philosophy is based on a multi-faceted approach to research, where many tools and methods are brought together. One example is the creation of an Alzheimer’s disease mouse model in 2000, which develops amyloid plaques in the brain, exhibits cognitive and memory impairment and accelerated mortality. The mouse model, known as TgCRND8, became famous and has been used around the world. In one of these studies, conducted by Tanz researchers, vaccination of TgCRND mice with the amyloid beta peptide elicited an immune response that partially prevented or reversed AD-related cognitive and memory impairments.This finding paved the way for ongoing clinical trials of second generation vaccines.

Immune reagents also play a role in ongoing ALS research at the Centre, exploring the therapeutic use of the first antibody that selectively labels the misfolded form of a protein implicated in this disorder.

Because proteins usually work in small interactive groups, once a gene has been linked to a disease, it can be very enlightening to identify its “partners in crime,” says Tanz researcher Gerold Schmitt-Ulms, a Professor in the Department of Laboratory Medicine and Pathobiology.

When Schmitt-Ulms applied this strategy in 2009 to the prion protein, his team not only identified other proteins that bind to it, they also unexpectedly discovered the evolutionary origins of prion genes.

“This finding solved an enigma in prion research: it linked the prion gene, which had no apparent role aside from its causative involvement in an invariably fatal disease, to a larger family of genes of known function,” says Schmitt-Ulms. “The hope with a discovery such as this is that one can learn something that will be useful to devise a disease intervention strategy.”

An ideal drug for the treatment of neurodegenerative diseases would be one that could be taken in oral form, would easily pass into the brain through the so-called blood-brain barrier, be effective at dissolving amyloid plaques and, at the same time, not react with parts of the body it is not targeting. A few years ago, Tanz researchers identified a small sugar molecule, scyllo-inositol, which seemed to combine all of these features in tests on the TgCRND Alzheimer’s mouse model. Six years later, plans for a Phase III human clinical trial led by a pharmaceutical consortium are underway.

Despite the above, and many more contributions by the Centre, its success should not be measured by individual discoveries alone, cautions Fraser.

“While the initial discovery is important, it is incrementally adding to these contributions that have made a difference,” he says. “The Centre is designed as a place where people with very different skill sets and interests work together.

“Everyone has their own complementary interests and technological expertise, so each person has their own piece of territory, but all mesh perfectly into one working Centre.”

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