Team Player

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By Amber Lepage-Monette

As busy as he is, it’s hard to believe Dr. K. Wayne Marshall, PhD was excited about starting a company. But lo and behold, taking on a fourth job wasn’t going to stop this orthopedic surgeon, professor and team surgeon from pursuing a career in business.

A casual acquaintance with fellow physician Dr. David Caspari was the launching pad for the formation of ChondroGene Ltd. (Toronto, ON). Caspari brought Marshall together with cardiovascular genomics researcher Choong-Chin Liew, PhD to see if the two had common interests. “It was the most exciting hour I ever spent,” Marshall says.

“What I became aware of at that point is that there are these tremendously powerful tools. Things like gene sequencing and microarray were starting to develop — tools that were being used in molecular biology and in the Human Genome Project. But these weren’t tools that had really reached into orthopedic research or arthritis research yet,” he says.

Listening to Liew describe his genomics work with the cardiovascular system, and then describing his own work about joints to Liew, Marshall says both became excited about the possibilities of combining their work.

Homeward Bound
Born in Canada, but raised in the U.S., Marshall came back to Canada after finishing medical school to complete postgraduate surgery training at the University of Toronto (Toronto, ON). Though Marshall started his residency in general surgery, he ended up switching to orthopedic surgery and later took a job with his mentor Dr. Robert Jackson, who is often recognized as the physician who perfected and popularized arthroscopic surgery. Jackson had also been the team surgeon for the Toronto Argonauts until 1992, when he relocated to Dallas, Texas to be chief of the department of Orthopaedic Surgery at the Baylor University Medical Center (Dallas, TX). Marshall took over as Argos’ team surgeon around 1994.

Marshall says his life continued like this, working as a physician, an assistant professor in the department of Surgery at U of T’s faculty of Medicine, and team surgeon for the Argonauts, until 1998 when that fateful meeting brought him together with Liew.

The joint is an enclosed space, Marshall explains, so approaches such as gene therapy or stem cell therapy are safer to use compared to body-wide gene therapy. Realizing they could actually apply Liew’s work to Marshall’s area of expertise — the joint — got the wheels in motion.

“There would be an opportunity to do proof of principle types of experiments, and ultimately, therapies in humans in the joint that would probably lead to the development of systemic gene therapy. So that’s why (Liew) got excited in the joint as a model system to work in, and I got excited by the tools that he was using,” Marshall says. “So that was really the impetus for us to found the company.”

ChondroGene’s work involves characterizing gene expression in human cartilage cells, or chondrocytes, through the various stages of development — from early developmental to normal adult, and in progression of disease from early, to intermediate and end-stage osteoarthritis (OA).

As Marshall explains, the hope is that by understanding gene expression, they will learn the pathways that are important in the disease’s development. In understanding the disease’s development, they hope to eventually be able to control the progress of the disease.

This is key, as current therapies for osteoarthritis focus on treating the symptoms.

“We do not currently have any treatments that actually modify the disease process itself — either slow it down, stop it, or, in an ideal world, actually reverse the disease process and help to regenerate new healthy tissue,” Marshall says.

“So there’s a lot of focus going on in the pharma and biotech worlds to try to develop treatments that will actually affect the disease process. But unless you understand the pathways that are driving the disease process, then you can’t find an appropriate target.”

New Directions
This is where ChondroGene’s $7.5-million deal with Pfizer Inc. (New York, NY) comes into play. In October 2002, the two companies entered into a research deal, whereby ChondroGene uses its own microarray technology to identify targets that can be used to modify the disease process. Pfizer uses ChondroGene’s genetic database to develop anti-arthritic compounds.

Marshall says he has heard some people question why a small Canadian company would get into such a deal, which appears to give the advantage to Pfizer, a company with which ChondroGene cannot compete.

“We’re not going to be a pharmaceutical company. We’re not in the business of trying to develop small molecule therapies,” Marshall says. “But what we are interested in is taking similar types of targets and using them for local treatments.”

Because osteoarthritis is localized in the joint, as opposed to being body-wide the way rheumatoid arthritis is, Marshall says there will always been a big market for localized treatment of the disease.

“So that way, we’re complementary to a company like Pfizer. We’re not in the same market,” he says.

ChondroGene’s deal with Pfizer also involves a new direction the company is moving into — biomarkers. Ultimately, Marshall says, the goal with osteoarthritis, as with many diseases, is to be able to diagnose the disease at a much earlier stage, and also to be able to know which patients will respond to what treatment. One thing that is frustrating to a physician is knowing that there are subpopulations of patients who respond to treatment differently, Marshall says. Using anti-inflammatories for osteoarthritis treatment as an example, Marshall points out that there are some patients for whom all anti-inflammatories work, some patients for whom no anti-inflammatories work, and still other patients for whom some anti-inflammatories work, and others don’t.

“Yet we have no way of predicting in these patients and in an individual patient, what’s the right treatment to use. Yet we know that these subpopulations are there. So much of the treatment, really most of the treatment that we use today, is a shotgun type of treatment,” he says.

Though Marshall says ChondroGene’s focus will always remain on osteoarthritis, it is starting to use these biomarkers for other disease areas as well.

“That’s not to detract from the roots of the company,” Marshall says. “We’ll continue to be working with Pfizer in the area of OA, but we definitely are going to be broadening in other disease areas.”

Role Reversal
Though Caspari, Liew and Marshall founded the company together, eventually it was Marshall running things at ChondroGene. In the initial stages, both Liew and Marshall held roles as chief scientists for basic and clinical science, respectively. Caspari’s business background, Marshall says, led him to take on the roles of president and CEO.

But not long after the company was started, Liew was asked by Harvard Medical School (Boston, MA) to set up a cardiovascular genome unit — of which he is currently director — at Brigham and Women’s Hospital (Boston, MA). In December 2001, Caspari decided to move on, and Marshall took over as president and CEO in January 2002, and has led the company ever since.

Taking over as president and CEO was a decision made with some reservation, Marshall says. “It was certainly something that I wasn’t comfortable doing unless I had the appropriate support,” he says, stating that building the board, with the addition of Rory Riggs — former president of Biomatrix Inc., which was later acquired by Genzyme Corp. (Cambridge, MA) — as board chairman, was an important factor for his taking over as company head.

Despite his reservation, Marshall says he found himself more suited for the role than he expected.

“I guess there (have) been things in my background that I’ve found are very useful in a situation like this. Even though I don’t have formal business training, a lot of the principles of building a company are the same as building an effective team in the operating room, or building an effective lacrosse team,” he says. “And that’s the exciting part, because it’s predicated on getting the right people.”

Marshall says though he is a combination of businessman and clinician, roles that blend well, he is also realistic about the future.

“I think it’s hard to know how this will evolve,” he says. “I won’t necessarily be the right person to be here forever either. As the company evolves, I think you always have to look, step back, and say, am I the right person to be doing this?”

Long Days
Though he says taking over as president and CEO was exciting, Marshall admits that wearing several hats can be taxing. “I think that if I didn’t have a lot of outstanding people that I’m working with, both at the hospital and here, it would be impossible,” he says. “(You) certainly have to be a lot better about organizing your life . . . They aren’t 40-hour weeks, that’s for sure,” he laughs.

Balancing his several roles presents some challenges, but Marshall again points to his clinical experience as good preparation for the juggling act.

“I guess it’s no different than it (has) always been, in that to try to be an academic, clinician-scientist, is always a challenge because you’re trying to write grants . . . at the same time you’re trying to keep your clinical practice going, and I think as the science has gotten to be more complex and technology’s more expensive, that’s a model that’s harder and harder to follow,” he says.

“In many ways it was just sort of tweaking what I’d been doing for a long time, except now being in a position to have the resources where there was the opportunity to really be able to make more of a difference, as opposed to being able to publish some papers and do some interesting little projects,” Marshall says. “But now we can do things that were potentially much more significant and really have an impact on the way we treat patients.”

Marshall says when it comes to giving others advice, he doesn’t have all the answers.

A few elements that do come into play in creating a successful company, Marshall says, are having a clear focus, both clinically and scientifically, and a willingness to adapt your plan as the company evolves.

But most importantly, he says, success is predicated on who you have.

“You can have the money, you can have a plan, but if you don’t have good people, you won’t be successful,” he says.

In the end, there is one thing Marshall is certain of.

“I know that I’ve never been as excited about what I’m doing as I am now,” he says.

“I’ve always enjoyed doing research and I’ve always enjoyed clinical work, but I just think that this job at ChondroGene now just kind of brings in all of the things that I like,” Marshall says. “It brings in the clinical side of things, it brings in the science and it brings in the team-building that goes along