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Reinventing Research

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Novartis'' move to Cambridge is more than just a latitude adjustment. It''s a whole new approach to drug discovery.

By Aaron J. Sender

 

He may not seem like the right man for the job. In fact, when Novartis chief executive Dan Vasella called Mark Fishman last September in an attempt to lure him into heading the pharma’s global research operations, Fishman was startled. “I think you dialed the wrong number,” he told his future boss.

Fishman certainly has the scientific credentials. He’s a physician and chief of cardiology at Massachusetts General Hospital and a Harvard med school professor. He built the university’s globally renowned Cardiovascular Research Center from the ground up, and authored a widely used med-school text book, “Medicine.”

The aptly named Fishman has also made a name for himself by bringing the zebrafish to the forefront as a model organism. But there is something glaringly absent from his 18-page CV: pharmaceutical industry experience.

“I had never done consulting for big pharma. I had not been on any boards of pharma,” says Fishman. “I really hadn’t been in this world at all.”

Yet perhaps someone with Fishman’s background and naiveté about the conventions of drug development is exactly what the ailing pharmaceutical industry needs. Still mired in the traditional chemistry-based approach, pharmaceutical companies have yet to effectively translate genomics and related technologies to faster, cheaper, and better drug discovery. Despite increasingly pouring cash into R&D and new technologies, how to incorporate the new biology into the current drug-making process remains unclear.

Not tainted by the age-old conventions of commercial drug discovery, Fishman offers a fresh perspective only an outsider could provide. In fact, Novartis doesn’t see the hole in his resumé as a liability, but rather an asset. “Having been for several decades in the pharmaceutical industry, you have Pavlovian reflexes,” says Alex Matter, head of translational medicine at Novartis. “But [Fishman] tends to say, ‘Why do we do that? And why do we need that?’ And then you start scratching your head — maybe we don’t.”

Novartis is certainly not the first to pluck an academic star to head its research. Back in 1975 Merck snagged Roy Vagelos from the Washington University School of Medicine, where he was chair of the biochemistry department. Ten years later he became CEO and led the company through some of its most successful years. And less than two years ago Merck, brought in MIT protein expert Peter Kim to lead its research efforts.

But Fishman faces an opportunity no one in big pharma has had before: the chance to build a drug company’s research institute from scratch and experiment with new ways to re-engineer drug discovery for the post-genomic era.

“It will be a pilot for a different way to do research and development,” says Jörg Reinhardt, Novartis’ head of global development.

Public-Private Limbo Dance

So what does Fishman have in mind? “It would be a little premature for me to be very specific, to be honest,” he says. “I am not yet in suggesting mode ... I’m in listening mode.” But one thing is clear: At the core of his experiment is a mission to dismantle the barriers between traditionally secretive and insolated pharmaceutical research and academia. “If your goal is to reinterpret the human genome in functional terms, you’re not going to do it yourself. You need to have colleagues,” says Fishman. “My hope is that by interpolating these cultures we can really do great things.”

There’s no better place to perform this experiment than Cambridge, Mass. At 100 MIT Technology Square — on the corner of Main and Fulkerson Streets — men in white plastic hats and goggles saw and weld among the dust and rubble, preparing the first building of the Novartis Institute for Biomedical Research for its opening early next year. The eight-floor, 255,000-square-foot building is shaped like a D. The flat side holds the building’s atrium, which abuts 200 Tech Square, home of MIT’s lab for computer science and artificial intelligence. The windows from the curved side provide spectacular views of Cambridge and Boston, home to some of the world’s brightest scientific minds and most eminent hospitals. The building, which is also directly across the street from the Whitehead Institute, will hold lab space for 400 scientists. Fishman will hire another 500 over the next five years.

“[We] needed to put the institute in an area where it was convenient and easy to interact with hospitals and academia,” says Fishman. “If you’re right across the street, it could make it easy for people to use your facilities.”

Fishman would like the new research institute to examine how low the academic-pharma barrier can go. He envisions intimate collaborations, joint seminars, Novartis scientists with professorships at universities, and professors working on projects at Novartis. “Secrecy often inhibits rather than protects the growth of ideas,” he says. “The culture inside NIBR will reflect academia.”

There are many advantages to rubbing shoulders with non-profit neighbors. First, the big science required to study pathways and entire living systems cannot be tackled in isolation. The proximity also expands the number of minds available to provide valuable input. “If you’re open to academia, you’re also open to their criticism, which is very important,” says Fishman. “If you’re open you’ll also attract the best and the brightest. You become part of the community.” And by bringing hospitals into the equation, “you are able to set up meaningful interactions with physicians and refine your directions early in the discovery process.”

Fishman admits that breaching the wall won’t be easy. There is resistance on both sides. “We undoubtedly will need to address issues of intellectual property,” he says. “You have to figure out what makes sense to patent and what doesn’t.” For example, he believes that there’s no benefit in locking up knowledge of molecular pathways and disease models in animals. “In the long run, if you’re smart, focused, and have the data together, you can then make your medicines that will give you the proprietary coverage that you need,” says Fishman, who seems to prefer the word “medicine” to “drug.”

Not bogged down by existing infrastructure, Fishman is free to design the new facility to take full advantage of the genomic revolution. One approach he is eager to try is systems biology. “We need to figure out how to reassemble the knowledge of the genome into the intact animal, because that’s what we treat,” he says. “Whatever we learn has to be integrated into systems biology.”

This approach also requires a new kind of informatics: computational systems biology. “It’s been in our plans for some time, but now we’ve got the opportunity to actually do something about it,” says Novartis head of informatics and research knowledge management Manuel Pietsch. Most leading-edge software development in this area is still in academia. “Because we’re now in Cambridge we can hire people in the local academic institutions and have collaborations with people there.” Up to 60 of the first wave of hires will be in IT and computing, according to Pietsch. “Of those I’d like to have 20 to 25 in the bioinformatics area,” he says.

Another area Fishman would like to address is patient phenotyping. “When I think about pharmacogenomics, the issue there is not so much the genotype. That we can do,” he says. The issue is being able to non-invasively sort related diseases by phenotype. “You certainly can’t do good clinical studies if you can’t sort out one phenotype from the other,” says Fishman.

“It’s not that anything I’m saying is totally new,” he says. “It’s just that we have the opportunity to build it from scratch.” In fact, anybody can incorporate these concepts into their research. “But it’s a lot harder than if you can start with a fresh canvas and then paint,” says Fishman. “You can do it. You can get the same picture. It just takes a lot longer.”

Making the Move

Novartis has other reasons to move its research headquarters to the US. The pharma is the outcome of a $27 billion merger — that in 1996 was the biggest in the industry’s history — between two stuffy Swiss laggards, Sandoz and Ciba-Geigy. The Cambridge move represents the next step in its evolution as a major player.

With $19.1 billion in sales last year, Novartis ranks seventh among its competitors. But only about 45 percent of its business comes from the US, the most profitable and fastest-growing pharmaceutical market. That share isn’t enough to compete with the likes of Merck and Pfizer, which boast more than 60 percent of US sales.

“The US is really the only market of size that grows faster than GDP,” says Bernstein pharmaceutical analyst Catherine Arnold. “Despite the pricing pressures, there is still more pricing flexibility in the US than other places. So increasing penetration in the market helps Novartis in terms of top- and bottom-line growth.” Add to that a friendlier business climate and greater government spending on biomedical research than in Europe, and the move makes perfect sense.

At first Fishman was reluctant to leave his ivory tower. “I am really perfectly happy in this academic cocoon,” he says. Dressed in a blue shirt and khakis, Fishman gazes out of his Mass General office window overlooking the Charlestown Navy Yard as he composes his sentences. “My whole life was around Harvard,” he says. Except for a two-year stint as a neurobiology postdoc in the NIH lab of Nobel laureate Marshall Nirenberg, Fishman, 51, has spent the last 30 years at Harvard, beginning with med school. His interest in biology budded in adolescence, when he spent summers as a lab tech at a marine biological station in Bar Harbor, Maine.

Fishman worked his way up through the Harvard system — joined the faculty, ran his own institute, and became chief of cardiology at arguably the world’s most reputable hospital. “Once you’ve been chief of cardiology at Mass General, well, that’s pretty much the pinnacle of the profession,” says Nadia Rosenthal, a former faculty member at Fishman’s cardiovascular institute, now head of mouse biology at EMBL in Rome. “The comfort level here is fantastic,” says Fishman.

It wasn’t until after six months of persistent wooing by Novartis CEO Vasella that Fishman began to think that he was faced with the challenge of a lifetime. He became convinced that Vasella was serious about letting go of convention and overhauling the drug discovery process. “He’s very open to new ideas about science,” says Fishman.

Vasella also assured Fishman that he would not be expected to churn out drugs right away and that he would have the flexibility change course midstream. “But for me the major issue was [whether] these concepts that Dan espoused and I shared permeated the company. So that required that I go back and speak with the board of directors and some of the leadership,” he says. “I got the sense that they genuinely are willing to do this experiment, that they’re willing to try new ways of doing things.”

Fishman says he finally realized, “we’re in the midst of a revolution in science the likes of which we’ve never seen before. Maybe the next stage is to take this to making medicines.” On April 24th he accepted the position.

Risk and Bliss

Although an unknown in the pharma world, those familiar with Fishman say he has the personality to shake up and challenge established ideas at an organization. At meetings he’s the first to highlight the absurdity of the discussion. “It’s part of his take on life. If he hadn’t been vaguely amused by all the pomp and circumstance surrounding the job he just left, he wouldn’t have survived it,” says Rosenthal. “He took the whole thing tongue-in-cheek when it came to the obvious self-importance that Harvard tends to wallow in.”

Fishman has also shown that he is not averse to taking risks. “He is one of those people who isn’t scared to try something that’s not an obvious sure shot,” says Rosenthal. For example, when Fishman decided he would use zebrafish as a genetic model, “people thought he couldn’t do it,” she says. He had no sequence or genetic maps to work from, but he prevailed. By introducing random mutations into the fish’s sperm, he has identified more than 100 genes related to cardiovascular development, many of them novel. “It turned out that many of these mutations looked like human disease,” says Fishman. The annual zebrafish conference, originally hosted by Cold Spring Harbor Laboratory, became so popular that it was forced to move to Wisconsin.

Of Fishman’s venture into drug discovery, Rosenthal says: “He’s been taking risks all along. This is just his next risk.”

But Fishman knows that this risk has more at stake. He is entering an arena he knows little about. “I have an immense amount to learn: how companies work, how drugs are discovered,” he says. “I’m still on a very steep learning curve.” It’s too early to tell if his lack of familiarity with the drug business will hurt his efforts. Novartis executives, however, are not worried. Scientists with pharma experience? “We have lots of those,” says Paul Herrling, who headed research before Fishman jumped aboard and has now been bumped up to head of corporate research.

Translational medicine head Alex Matter, who as head of oncology led the team that brought the breakthrough cancer drug Gleevec to market with just two-and-a-half years of clinical trials, was promoted to his new position to compensate for Fishman’s lack of drug development experience. “He is actually there because of my recognition that there’s this gap in my knowledge called ‘how to make a drug,’” says Fishman. “He’s going to help me ensure that we go from the discovery process to drugs continuously.”

It will take years to see whether the experiment pans out. And until Fishman’s changes take effect, he will still have the responsibility of keeping Novartis’ pipeline flowing. But if a fresh start at drug discovery turns out to be a successful model for integrating genomics into the process, and if ignorance of drug development does indeed turn out to be bliss for Novartis, it’s a safe bet that others will soon follow its lead.

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