Getting To the Heart of the Matter

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By Amber Lepage-Monette

Trying to understand the link between the genetic determinants and environmental determinants of heart, blood-vessel and lung disease is no easy task. It is one that requires great skill, knowledge, and also, great computing power. And it is the work of some 250 staff, including principal investigators, researchers and students, at the James Hogg iCAPTUR4E Centre for Cardiovascular and Pulmonary Research (Vancouver, BC).

Meticulously combing through data, researchers at the iCAPTUR4E Centre — which stands for Imaging, Cell Analysis and Phenotyping Toward Understanding Responsive, Reparative, Remodeling and Recombinant Events — search for answers to questions about the various factors, such as genetic, ethnic, economic and social influences, that contribute to a number of common diseases. Some of the conditions studied include asthma, atherosclerosis, or hardening of the arteries, and chronic obstructive pulmonary disease, or COPD.

“We have both individual, investigator-driven programs, as well as group programs, which are focused on these issues, and we are interested in the multiple levels at which the genetic influences may participate from the level of the genome and its variation,” explains Dr. Bruce McManus, PhD, iCAPTUR4E’s co-director and a professor in the department of Pathology and Laboratory Medicine at the University of British Columbia (UBC) (Vancouver, BC).

iCAPTUR4E’s research also looks at the variations in gene sequences, as well as in RNA expression for a whole host of genes that relate to the conditions its scientific staff studies, McManus says. To do so, iCAPTUR4E uses technologies, such as cDNA microarrays or oligonucleotide arrays, which allow the researchers to look at the entire RNA expressome, and to study those processes in both human- and animal-cell models. The centre also examines which proteins are over- or under- expressed in disease, and how these proteins may be functionally altered.

Getting Started
Though the iCAPTUR4E Centre was officially opened in 2003, its foundation is decades old. Dr. James Hogg, PhD, a professor emeritus in the department of Pathology and Laboratory Medicine at UBC and a researcher at the iCAPTUR4E Centre, established the Pulmonary Research Laboratory at St. Paul’s Hospital (Vancouver, BC) in 1977. The Pulmonary Research Laboratory would later evolve into the McDonald Research Laboratories, with the accrual of other laboratories, and was renamed the iCAPTURE4E Centre at the 2003 opening.

McManus explains that the patient information that now makes up the iCAPTUR4E Registry comes in part from registries of patient information and human biological materials that both he and Hogg have been acquiring through their research since the late 1970s and early 1980s. Hogg’s data related to lung diseases, and McManus’s related to blood-vessel diseases.

“What we were able to do in the iCAPTUR4E Centre is to take those databases and those repositories and to harmonize them and to use informatics and a database strategy that has created what we call the iCAPTUR4E Registry,” McManus says.

The iCAPTUR4E Registry is a collection of registries of patient information that is integrated with banked tissue samples. Information collected through four main technology cores of the centre’s work is entered into the registry. These cores are the Molecular Phenotyping core, the Ultrastructural Imaging core, the Dynamic Cellular Imaging and Biophysics core, and the Organ Pathophysiology and Imaging core.

Within the Molecular Phenotyping core, gene and protein expression in human and animal tissues and cells is characterized and quantified. For the Ultrastructural Imaging core, the fine structural detail of tissues, cells and molecules is assessed using both transmission electron microscopy and atomic force microscopy. In the Dynamic Cellular Imaging and Biophysics core, events within a single living cell are examined as they happen using confocal microscopy, high throughput confocal microscopy and multiphoton confocal microscopy, among other technologies. In the Organ Pathophysiology and Imaging core, researchers assess organ structure and function in patients and in living, working organs.

Putting it all Together
The collection and inputting of this information is one facet of iCAPTUR4E’s work. The other is data integration — allowing researchers to analyse this data in a meaningful way.

“We have been working on a data integration strategy, in a collaborative relationship with IBM for the last two-and-a-half years, in which, for example, we have built a data integration engine,” McManus says. “It’s a software engine which allows us to bring extraordinarily diverse and complex datasets into the same computational space, or assessment space, so that we can run a number of either routine or special application tools on the data.”

Vancouver-based Jeffrey Betts, business development manager of Life Sciences with IBM Canada Ltd. (Markham, ON), explains that this engine, the iQ Engine™, is designed to make data analysis easier for iCAPTUR4E researchers.

“Its objective is to integrate, in kind of a natural language environment, a very disparate range of data types that iCAPTUR4E uses for its science,” Betts explains.

The iQ Engine brings together these microscopy images, annotations on the images, and molecular information, either genomic or proteomic, so that researchers can analyse the differing information together, Betts says.

With the natural language interface provided by the iQ Engine, the researchers “can interrogate these very broad and disparate types of data, can create associations and correlations amongst them in ways that, historically, iCAPTUR4E could not do before our collaboration with them,” Betts says.

Betts explains that when researchers look at the iQ Engine interface, they can choose different datasets from pop-down lists, and that datasets are named in nomenclature that the researchers use.

For example, Betts says researchers may look at datasets from a cohort from a particular study, such as on asthma, and may request to look at patient data from those within a certain age group, or those who are former smokers. Researchers can further detail their data search and analysis by adding what information they would like to see.

“Then they can add a third factor and a fourth factor into this correlation, so it actually manages a huge amount of complexity for them, allows them to do multivariate analysis and correlation studies amongst many datasets,” Betts says.

The iQ Engine uses a variety of software technologies, one of which is a research algorithm called FANO, which conducts undirected data mining.

“(FANO) looks for things that are statistically improbable,” Betts explains. “Either things that you wouldn’t expect to see but are there, or things that you would expect to see, but aren’t there. This is a powerful tool for this kind of translational research that these scientists are doing.”

The iQ Engine is also powered by DB2™, a relational database product that again allows information to be integrated. DB2 “speaks” an XML language — MAGE, or Microarray and Gene Expression language — that is associated with a new emerging standard called MIAME, or Minimum Information About a Microarray Experiment.

“That enables the integration of microarray experiment data easily into a broader data interrogation strategy,” Betts says.

Finding a Common Language
Technologies like the iQ Engine are providing iCAPTUR4E researchers with the means to tackle the problems that come along with analysing such a broad range of data. McManus points out that iCAPTUR4E research not only involves genetic research, but also linking that data to other factors.

“On the environmental side, the challenge is just as great as it is on the genomic or proteomic or molecular or cellular organismic side, and . . . there are many environments,” McManus says.

Environments studied by iCAPTUR4E include educational, ethnic, social, economic and physical, and McManus says each of those environments has multiple layers of data.

“I think one of the current challenges that we face, and that many other research centres and researchers in general face, is the need for either common nosologies or . . . a commonness of language around all of these different levels of organization and the systems that we’re now beginning to focus on,” he says.

Researchers at the iCAPTUR4E Centre aren’t the only ones to take advantage of or benefit from the work conducted at the centre. One of the main goals behind iCAPTUR4E research is the betterment of patient care. In the past, that aim has grown out of the centre’s philosophy that information should be shared, and that the research conducted at the centre is open.

McManus cites iCAPTUR4E’s research into the once-popular weight-loss drug fenfluramine and phentermine, more commonly known as fen-phen, as one example of this. Though the drug had already been recalled due to adverse patient reaction, iCAPTUR4E researchers were able to provide the hard evidence that links fen-phen to heart damage.

“The unique information about the heart valves that had been surgically excised from patients who had been on these drugs allowed us, for the very first time, to define for absolute certain that there indeed even was a specific lesion that was related to these drugs,” McManus explains.

Though the adverse side-effects were illuminated by the iCAPTUR4E research, other benefits from iCAPTUR4E research may be the ability to better understand drugs and patient reaction, and may therefore translate into safer drugs in situations like these.

“Even though these are very powerful at reducing body weight and there’s still a great deal of interest in the pharmaceutical industry in developing drugs in this class, the kind of information that we provided — and the subsequent studies we’re doing on the mechanisms by which this may occur — have helped to guide those people who might be thinking about combinatorial chemistry and what kind of changes need to be made in the molecules in order to produce safe anti-obesity drugs that would not indeed harm the heart valves,” McManus says.

Another example that McManus cites to show how other research centres, and in the end, patient care, benefit from iCAPTUR4E’s work is that of lipid reduction prior to surgery. Research conducted on the level of lipids present within artery walls of transplanted organs has been translated into policy at hospitals and surgical centres.

“That information, the unique information . . . was a significant part of the basis by which nearly all heart transplant centres, for example, now have patients on lipid-lowering drugs like HMG-CoA reductase inhibitors,” McManus says.

End Goals
Collaborative research, in the end, has a lot to do with iCAPTUR4E achieving its goals of better disease understanding and better patient care.

“The goal, ultimately of course, is to — from the very most fundamental question that one is asking through to better health — is to move your pieces of knowledge into some synthesis strategy that includes not only the information that you generate, but that of course is generated in other laboratories and other research centres,” McManus says.

When it comes to the centre’s collaboration with IBM, McManus says the company’s experience brought much to its contribution toward the development of the iQ Engine.

“We benefit from an organization rich in talented people, who are committed to similar goals. They, more in terms of providing platforms, hard- and software platforms, that enable researchers like ourselves,” he says.

Betts agrees that iCAPTUR4E’s goals are important contributions to health care.

“They’re trying to understand the molecular underpinnings of those disease states and we share this vision of prospective medicine with them, that eventually we’ll be able to inform patient care, with insights gained from a molecular understanding from each individual,” Betts says, “where we’ll be able to personalize health care based on their unique genetic makeup and that we’ll be able to better prescribe drugs that are effective and that aren’t toxic, and so we’ll save money and time and precious lives with them.”