Building a hospital for a different kind of patient

Amble through the freshly opened Toronto Centre for Phenogenomics (TCP) and a quotation from Walt Disney will likely bob around in your head. "If you can dream it, you can do it," said Disney. And then he added, "Always remember that this whole thing was started with a dream and a mouse."

The TCP's vision is also to blend dreams with small creatures. "We are using genetically engineered mice as a model for the human condition" is how Colin McKerlie, who is the TCP's chief executive officer, describes one aspect of the vision.

Specifically, TCP aims to become a place where anything that can be learned from a genetically engineered mouse can be applied to everything that isn't known about human disease.

But isn't the act of scientists studying lab mice and their genetics to learn about diseases almost ancient in its conceit?

Indeed. Genetic research has used mice since French geneticist Lucien Cuénot first analyzed the inherited colours of coats in the animals in 1902. And inbred mouse strains suitable for laboratory use began appearing around the same date.

But over the last quarter-century, what can only be termed a revolution in mouse gene manipulation has occurred.

"What we have been able to do over the last 25 years is go into the mouse genome and change genes at will - and change bits of chromosomes too," says Janet Rossant, chief of research at the Hospital for Sick Children.

You stop the functioning of one gene or reconfigure a slice of a chromosome and suddenly the confusing DNA software of life begins to make sense. A gene says by its silence, "I control this slice of development" or "Stop me and this and this and this happen." The "this," Rossant points out, is not simply normal embryo development for which she has earned an international reputation. It is also that myriad of diseases and conditions the existence of which is rooted in genetic mutations and malfunctions.

The ability to create mice with genes that can be disabled or eliminated by genetic manipulation - generally by altering the stem cells from which they develop - has to date produced more than 10,000 varieties of so-called "knockout" mice. These techniques have produced strains of mice that collectively lack roughly half the genes found in mammals. In 2007, the development of the knockout mouse technology was seen as so significant that creating it won Mario Capecchi, Martin Evans and Oliver Smithies the Nobel Prize in medicine and physiology.

Knockout mice are also an area in which Toronto researchers, most notably Rossant, Tak Mak and their colleagues, have achieved worldwide reputations over the past decade. Only they and their colleagues elsewhere were finding themselves increasingly log-jammed.

"We're into what has been called a paradigm shift in the post-genomic era of health research" is how Colin McKerlie puts it. "We've got the gene sequences of a variety of species, including the mouse and the human. But now we need to do what we're calling 'big science' and put those genomes to work. And that is not something that medical research has traditionally done in the past because 'big science' is multidisciplinary. Today, medical research is no longer a lone neurologist working on their simple neurological questions. Rather, it's a recognition that disease is multisystemic, and therefore disease research needs to be multisystemic."

The research model that was in place not only didn't recognize the need for collective biomedical research; in a way, it abhorred it.

"Previously, if you got stalled in your research and you didn't know where to go, you begged, borrowed or stole your way to collaboration. Maybe you knew someone who might - I should underscore 'might' - be able to help you with your problem. Someone who might give you access to a piece of equipment or research expertise that you needed to try to tap into and move your research forward," is how McKerlie, who was trained as a veterinary pathologist, depicts the Toronto medical research model of recent past.

So Rossant, then based at Mount Sinai Hospital, began talking to colleagues at St. Michael's Hospital, the University Health Network and the Hospital for Sick Children about doing something they had never done before - quite simply, creating a common research facility that all could use. "The idea was that we wanted to develop facilities and teams to enhance our abilities to do mouse genetics," remembers Rossant.

After many meetings with hospital administrators and researchers who had never come together to create a combined facility, Rossant says, "We put in a proposal and got initial funding in 2002. Then Mount Sinai gave us a site, and the rest, as they say, is history."

Well, maybe it's fairer to say history in the making at what is being described by some as "Toronto's research mall for mice."

What do researchers find awaiting them at their mouse research mall and what, pray tell, is phenogenomics?

"When you put together an organism's genetic material - its genome - with physical traits we can see or measure - its phenotype - you get 'phenogenomics,'" explains McKerlie about the latter.

The mouse breeding, mouse clinical testing, mouse imaging and mouse behavioural tests will all be conducted in the impressive four-storey, 11,000-square-metre TCP facility. So, too, will the freezing and unfreezing of mouse embryos and the pathological analysis of the mouse models for human disease. The $69 million building will eventually house up to 180,000 mice in 36,000 cages.

Medical geneticists will also have access to a kind of who's who of the latest and best technology that's out there. The machines available to researchers range from high-field MRI to high-frequency ultrasound biomicroscopes to microcomputed tomography to optical projection tomography to bioluminescence imaging to a prototype mouse embryonic-injection system. Most of this equipment is specifically modified for work on the small and delicate bodies of mice.

Together, this technology will be used in various specialty centres. One is devoted to imaging mice, another to preserving a variety of cells from mouse varieties. Two other centres have been given over to various aspects of the modelling of human diseases in mice.

If this sounds highly impressive, rest assured you are not alone in your awe. TCP recently won the 2008 Turnkey Conference award for best new or renovated laboratory animal facility in North America. Its signal attractive quality, as cited in the commendation, was that it wasn't a single research hospital's facility. Rather, it was a Toronto and, to a certain degree, international facility.

The Toronto building, which officially opened in 2007, has also become a place of envy for scientists worldwide, most notably in what has been over the last 75 years the epicentre of world science - the United States.

A New York Times story in March of 2008 reported that the Academic Medicine Development Company - a consortium of 28 medical schools, health centres and medical research institutes in New York state looking to grow and attract biomedical research - was planning to build a 4,600-squaremetre mouse research lab. It's goal? To create a science cluster as impressive as that created by TCP in Toronto.

With all this as a backdrop, TCP researchers have begun to use the facility to study how mouse models can help them understand the genetic roots of osteoporosis and blood and heart disease - and to develop new animal models that mimic multiple sclerosis, schizophrenia and other diseases of the brain and neurological system.

And they have also begun to appreciate how valuable synergy can be. Marc Grynpas, senior scientist at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, who studies bones and bone diseases, speaks almost rapturously about his ability to do research across disciplinary lines.

"The best thing is being able to collaborate with a host of people who look at things in very different ways. For example, I am collaborating with diabetes researchers to understand why some new diabetic drugs cause bone fractures. And we are using the knockout diabetic mice to see if we can come up with countermeasures to prevent fracturing," he says.

What's more, TCP is working on a business model where 20 per cent of its time and facilities would be given over to other academic and industry partners who also want to use the mouse mall.

With this in mind, how does the instigator of the TCP mouse dream feel about TCP being likened to Mickey and Disney and a scientific version of mouse-made dreams?

"That's nice!" Rossant writes with an exclamation-point emphasis in an email.

And one cannot help but feeling Walt and Mickey would have given an exclamation-point approval back to TCP.