Université Laval professor and medical geneticist Claude Laberge likes to think big – really big – and long-term, too. He is the chief architect of a recently launched survey that proposes to track the health and genetic information of 50,000 Quebeckers, with the resulting data, as well as blood and urine samples, made available to researchers over the next 50 years.
Dr. Laberge, who is now scientific adviser to the study, recalls that this ambitious project, called Cartagene, really began to take shape one stormy night in January 1999 in an Italian restaurant in Montreal. The small group of diners included Bartha Knoppers, now the study’s principal investigator and director of McGill University’s Centre of Genomics and Policy. Their idea was to build a map of the genetic diversity of Quebec’s people, using what was then state-of-the-art technology: DNA chips developed by McGill researchers. (The project’s name is officially spelled CARTaGENE, playing on the words “map” and “gene” in French.)
For Dr. Laberge, whose father and grandfather were also Quebec physicians, Cartagene embodied a dream he had harboured all his professional life: to exploit several decades of genetics expertise and knowledge of the human genome for the benefit of human health.
“We don’t want to miss the train,” he insists. “We should be at the forefront of producing and understanding this type of genomic information, so that we can put it to use as fast as possible in health policy, medical screening, prevention and validation of treatment, for the benefit of the whole population of Quebec.”
A great optimist about the promise of genomic research, Dr. Laberge recalls that the medical successes of the 20th century were largely based on advances in observational biology, physiology and experimental medicine that began in the late 19th century. These approaches, he says, helped give us the means to treat and prevent many diseases. However, they’re based mainly on the analysis of so-called “phenotypes” – outwardly observable sets of traits of organisms produced by the interplay of genes and the environment.
Those conventional methods do not zero in on the underlying chemistry of life.
Watson and Crick’s groundbreaking description of DNA’s structure in 1953, and the subsequent development of molecular genetics, raised an intriguing question for Dr. Laberge: If traditional observational biology could yield such major scientific progress, what future advances might be possible if more research were based on the very thing, DNA that “controls and writes the biology.”
While he sees Cartagene as a bold and logical step in the evolution of medical science in Quebec, Dr. Laberge also believes it to be a means of using public resources more efficiently, as it reduces unnecessary competition for research dollars.
Dr. Knoppers, too, stresses the importance of research efficiency through resource sharing. Besides serving as the project’s principal investigator, she is also founder and chair of the Public Population Project in Genomics (P3G). This consortium helps researchers in many countries to harmonize their genomics work by sharing research methods and data as well as policies and procedures related to biobank access, governance and research ethics. In effect, says Dr. Knoppers, P3G puts an international “toolkit” at the disposal of projects like Cartagene. It helps ensure the same types of variables are covered by different research teams and that the resulting data are comparable across countries and projects. As a result, scientists are able to draw on a much larger data pool (which improves accuracy) and in some instances get meaningful research results much faster than if they were working only with their own study data.
Cartagene is both a beneficiary of P3G and a resource for it. To date it has fielded several requests from P3G member biobanks in various countries for information on procedural, ethical and legal frameworks. The Quebec project is also part of a larger national study of disease, the Canadian Partnership for Tomorrow Project, known by its acronym CPTP. This study, with a special interest in cancer, brings together five cohorts across the country, in British Columbia, Alberta, Ontario, Quebec and the Atlantic region.
“The value of Cartagene’s participation in CPTP includes the extensive experience in study recruitment and biobanking that they bring to the table,” says Elizabeth Eisenhauer, who chairs the Research Advisory Group of the Canadian Partnership Against Cancer, a co-sponsor of CPTP. Dr. Eisenhauer says that Dr. Knoppers has provided leadership “on aspects of ethical, legal, social issues and privacy critical to the successful implementation of this Canada-wide effort.”
After completing Cartagene’s start-up activities last spring, Dr. Laberge and his team launched the first phase of the project at the end of July. The project’s institutional home is at Université de Montréal, with Phase A funding coming from Genome Canada and Génome Québec.
Phase A centres on the collection of biospecimens and personal information from an initial cohort of 20,000 Quebeckers between the ages of 40 and 69. These are all volunteers from a large random selection of people registered with Quebec’s public health insurance agency, the Régie de l’assurance maladie du Québec (RAMQ). Volunteers come from four urban areas: Montreal, Quebec City, Chicoutimi (Saguenay) and Sherbrooke.
Apart from the relatively large size of the research cohort, several other features make Cartagene especially valuable to researchers, says Philip Awadalla, the project’s scientific director and a professor in Université de Montréal’s department of pediatrics.
First, the project is collecting not only genetic information (via blood samples) about the volunteers, but also a good deal of non-genetic information, ranging from lifestyles to medical history and demographic factors.
“What makes Cartagene stand out,” says Dr. Awadalla, “is that it’s well characterized in terms of environmental variables and clinical information that’s being collected across the four different sites in Quebec. This speaks to the genetics-by-environment interaction that is potentially important in the development of chronic disease, and how that might vary throughout Quebec.”
A second and especially novel feature is that the researchers are extracting RNA (ribonucleic acid) as well as DNA (deoxyribonucleic acid) from the blood samples. “Most big case-control studies don’t collect RNA,” says Dr. Awadalla. RNA is a signature of gene expression – “how often genes are turned on or off” – which means it can provide biomarkers for disease diagnosis and prognosis. Specimens are being stored centrally at a biobank in Chicoutimi operated by Génome Québec and the Centre hospitalier affilié universitaire régional de Chicoutimi.
A third special feature, from the viewpoint of the project’s usefulness to research, is the common ancestry of the bulk of the 20,000 volunteers. Although the cohort includes Quebeckers from various ethnic and racial backgrounds (especially in the Montreal subgroup), the great majority are French Canadians. For some kinds of research, the common genetic heritage of participants makes it easier to tease out environmental contributions to either good health or the development of chronic disorders. When looking at genetics-by-environment variation, “it’s nice to know you’re not confounding your observations by looking at different ethnicities,” says Dr. Awadalla.
The relatively homogeneous nature of the cohort makes it possible to do so-called “genetic linkage analyses.” In this case, researchers identify associations between, on the one hand, genes shared by members of a family and, on the other, genetically complex disorders such as heart disease, hypertension and diabetes.
Dr. Laberge points out that these kinds of associations could help identify at-risk individuals who might otherwise go unnoticed by physicians. For example, certain genetic profiles increase people’s risk of heart disease, yet these “silent individuals,” as he calls them, have normal cholesterol levels. “We would like to know where these people are,” says Dr. Laberge, “and eventually ensure that if there’s a family history, such a genetic profile becomes part of the evaluation by the doctor.”
Several projects had been approved by Cartagene as of mid-February. Among these are a methylmercury study by researchers at Université Laval and a project by Dr. Awadalla that will investigate how rural versus urban lifestyles affect the occurrence of chronic diseases.
The participant interviews and collection of biospecimens from the initial cohort of 20,000 are expected to be completed by the end of October, which also marks the end of Phase A funding.
The fate of Phase B, which would add 30,000 recruits to the cohort and expand the study’s coverage to other regions of Quebec, hinges on Phase A progress. Given the potentially long timeframe of the project, its financial sustainability is of great concern to the project leaders.
In any research where highly personal information is made available to researchers for analysis, ethical considerations are paramount. Cartagene has put in place extensive safeguards for appropriate use of the project’s resources, says Dr. Laberge. For example, all survey information in the databank and biobank is to be double-coded and encrypted. Codes will be changed for each partner organization given access to the information. Every transmission is secure and encrypted to protect the identity of volunteers in the study cohort.
Who gets to see and use Cartagene’s resources will also be tightly controlled. Each researcher or research team wishing to tap the database or gain access to blood and urine samples must negotiate an agreement. This will include provisions for sharing the results of that research with Cartagene so that these results can be made available to other researchers in the future. “We won’t provide access until our [review] committees know what the research project is, what the researchers want to do,” explains Dr. Laberge.
This strategy is not intended to prevent users from patenting inventions arising from the use of Cartagene’s genetic data and biospecimens. “The only way to get products that are helpful for certain health problems in the population is through patents,” says Dr. Laberge, noting that making products isn’t a role that Cartagene can play. But it can provide good data, he adds: “We believe that this is the fastest way to get population information to the producers of services, tests or medication, who then come back to help the population that provided the data.”
It’s all a matter of “public citizenship”, he adds. “Imposing these conditions will make researchers think about what they’re doing, about the fact they’re using publicly funded infrastructure of good quality which they themselves don’t have to set up. They will either take the corporate risk of sharing their results, or they will say, ‘No way, goodbye, we’ll go elsewhere.’”
One scholar observing Cartagene has publicly suggested that there is a need for an independent watchdog body to ensure public accountability and ethical use of the project’s resources. Dr. Laberge welcomes such a move, but he notes that a body with a similar mandate was set up during the formative stages of Cartagene and was disbanded by the Quebec government after three years of operation, on the grounds that there were already sufficient governance structures guiding and overseeing Cartagene. These include the provincial health insurance plan (RAMQ), as well as the Quebec agency charged with protecting access to information and privacy, and various university ethics committees.
“We’ve tried to be transparent in everything we do,” concludes Dr. Laberge. “We’re not hiding in the woods here.”
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Funding for Phase B
Creating an infrastructure for a 50-year project from short-term grants is “not the way to sustain it,” says Claude Laberge, Cartagene’s founder and scientific adviser. But he believes the project’s track record to date – in designing surveys and privacy safeguards, collecting information and biospecimens from volunteers, developing software, training nurses and other staff, and harmonizing efforts with other Canadian and international research groups – is a good basis on which to build support for Phase B. It is one of the reasons Cartagene staged a public forum on its work last December in Montreal. That meeting brought together dozens of research partners, government representatives, journalists and volunteers from the research cohort. “We were there to answer their questions,” says Dr. Laberge.
Given all that’s been learned in project preparations and the first part of phase A, says Dr. Laberge, “I think the next 30,000 [participant files] will cost much less to produce than the first 20,000 because we’ve now got the equipment, the software, the database, the biobank in Chicoutimi.”
Some funding is expected to be available beginning in 2011 from the Canada Partnership for Tomorrow Project (CPTP), to allow for follow-up interviews. Although Cartagene has requested further support from Genome Canada and Génome Québec, broader funding for Phase B of Cartagene has not yet been announced.