Searching for gene-based vaccines

When Jack Gauldie is asked what it was like to do research at McMaster University's Faculty of Health Sciences in the early 1990s, he is blunt to the point of bitterness. "It was a case of managing decay," he remarks.

On one level, the comparison might seem like an oxymoron given that Gauldie was the chair of the department of pathology at the time, a position often charged with tracking the body's illness and decay. But the actual decay he is referring to pertains to the university's physical property, the operating funds that were provided to support research and the erosion of the hopes of the many scientists who believed they could truly do world-class science. "The order of the day was gloom and doom," he remembers.

Then along came the Canada Foundation for Innovation, the Ontario Research Development Challenge Fund (ORCDF) and OIT. Thanks to these programs and their successors such as the Ontario Research Fund, we now have McMaster's Centre for Gene Therapeutics and its - the word is carefully chosen - products.

In the wake of increased funding and a new lab, a garden of research is now blooming. A gene-based vaccine for SARS has been developed. So has a gene-based vaccine for breast and skin cancer, as well as a vaccine for chronic lymphocytic leukemia and a new gene-rooted vaccine for tuberculosis.

How do these work? One of McMaster's approaches is to piggyback vaccines onto the common cold virus, allowing them to be more efficiently and safely delivered against infections such as the SARS virus.

Another approach that grew out of research modifies immune-activating cells found in the body with the goal of putting them into people with cancer. The hope is that these modified cells will trigger the body to produce immune cells that specifically seek out cancers.

"Tumours avoid immune attack by convincing the immune system that they are normal, a wolf in sheep's clothing" is how Jonathan Bramson characterizes the past research. He is the McMaster researcher who now leads a group of scientists across the country who are studying the phenomenon. "Our strategies are to teach the immune system how to spot the signs of the wolf. In this way, the tumours will no longer be able to hide, but the healthy tissues will be left untouched."

For the moment, the age of McMaster research decay and gloom and doom is over.

In Gauldie's mind, two parallel truths make what is happening at McMaster quite interesting. One truth concerns the twists and reconfigurations of science that have led McMaster's research to the brink of successful gene-based vaccines. The other, the changes in thinking and ways of acting that were required to get it there.

Getting to where McMaster currently is was a direct result of the institute almost falling on its face in the beginning. The original application for money to construct what would become a 5,800-square-metre, two-floor facility was turned down by CFI in 1998. This was disheartening to Gauldie and his associates because the proposed facility was going to be the first new research space McMaster had built since the early 1970s.

It was such a disappointing moment that at the time Gauldie told The Hamilton Spectator that he feared his research team would have to relocate somewhere else.

Why the failure? Initially, Gauldie blamed the federal government's lukewarm support of science. "We've become a Third World science country," he told the Spectator. Now, he sees things quite differently.

"Frankly, at the time our words were wrong, not our concept, not our content, but our words," argues Gauldie in his crowded fifth-floor office.

The so-called word problem was that the institute was describing what would later turn into its gene vaccine research as "gene therapy" because, says Gauldie, "There was a big buzz about gene therapy." The buzz argued that many diseases are caused by malfunctioning genes, so the way to cure them is to insert healthy, functioning genes into a sick person's body.

The problem was that not only would gene therapy turn out to be much, much harder than people originally thought, but everyone and his cat at the time was proposing to do gene therapy. "We didn't differentiate ourselves from anybody else. We didn't adequately describe what we had done, would do, and where we were going," says Gauldie.

So the next time the group made an application for a new facility, the words "gene therapeutics" were used in place of the words "gene therapy." This captured the thrust of the gene-based vaccines they were already working on and described the hoped-for directions their future research would go.

Beyond a change in words, it was necessary for basic researchers involved in the project to appreciate that the context in which they were going to do future research had shifted.

Applying for money to construct new facilities was quite different from making grant applications where the mantra was, says Gauldie, "Here is my basic question. Here is why it is important. Here is how I am going to address the question."

Now researchers had to ask themselves, "How might I exploit what I do commercially?" Originally the McMaster people didn't frame their proposal to coincide with the federal and provincial governments' view that this was important. "Then people began to think about how to position the question they were asking at the basic level into the bigger scheme of something that made commercial sense" is how Gauldie describes the change in thinking that went on.

McMaster had to rethink where the money to support their research might be coming from. While CFI and OIT promised 80 per cent of an institution's new infrastructure funding, there was still what some have called the "missing fifth" - the 20 per cent that had to come from other sources. Often, this came in the form of technology donated by computer companies and other businesses. That was not the case with this project. The proposed building of the centre helped trigger at McMaster one of the largest charitable contributions - if not the largest - ever made to a Canadian university: the $105 million gift given by Michael DeGroote in 2003.

The result? The building housing the Centre for Gene Therapeutics named in DeGroote's honour and the production of what Gauldie now views as a leveraging snowball effect.

"If the university hadn't begun this structure, I don't know how successful it would have been in gaining the donations it has. I wouldn't be surprised that an CFI/OIT initial investment has been magnified at least tenfold, if not fifteenfold," he says. All good, says Gauldie, but then he is asked what has truly come out of this work. Is there anything you can point to and say there's a cure? Are there a suite of companies that have been spun off from the research here? Are there practical applications the governments wanted?

No, he admits. None of McMaster's products and procedures have made it through what is sometimes called the Valley of Death of drug development; that is, the Phase 3 clinical trials in which the substances must show a significant positive effect on human diseases or conditions.

Moreover, he sadly points to the fact that two or three biotechnology companies that spun out of his institution's research have not survived in the marketplace.

Why? Unlike engineers or computer scientists, basic medical researchers aren't in the business of inventing what Gauldie describes as "widgets that are easy to sell." These are things "you already know your customer for. In health care, and often in basic health research, there aren't realistic buyers out there."

Basic research, however much you want it to be applied, often remains basic. We ask questions about how things work and sometimes why they don't. It's only when we get important insight into these questions that we may begin to formulate applied solutions.

Nonetheless, announcing this isn't the same as McMaster scientists returning to their previous model of research for the sake of research. Ask what he wants to come out of the research in 10 years, and Gauldie says that papers published and citations and even a Nobel Prize always matter, but so too does the economic future of the once industrial and now gradually de-industrializing community in which he lives.

"In a decade I want to be able to sit down and talk about the success of being able to establish biotechnology companies as spinoff interests from the various initiatives were funded by OIT and others in life sciences. The biggest employer now in Hamilton is the health care/university sector. We have to get some spinoffs that make some commercial sense associated with that," he says and then adds with vehemence, "In Hamilton we know that we have to commercialize. It's the only thing Hamilton's going to grow on."