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The Translational Trend


It's just a new buzzword, you tell yourself. The term, the hype, the misdirected federal funding — one day it will all go away.

But translational medicine is in fact not going to go away, if the experts who spoke with Genome Technology are any gauge. The push to drag research from basic labs to the clinic has never been bigger. With major investments from NIH and pharma, as well as some early successes in the clinical world, translational medicine — an amalgam of pharmacogenomics and other tools designed to bring research advances to the patient in the form of better medicine and diagnostics — is proving that it's got some staying power.

"When people talk about pharmacogenomics, there's always this hype around it," says Michael Phillips, director of the pharmacogenomics center at Genome Quebec and the Montreal Heart Institute. "I really think genomics is going to have a huge impact on healthcare. We're just at the cusp of what I would call the next revolution."

And it's about time. Jorge Leon, a pharma veteran and biotech consultant, says the slow pace of clinical impact is what's necessitating this approach. "In the field where I'm working, epigenetics, there have been 5,000 papers published recently. Why is that incredible cascade of basic research information translating so slowing into … the health gain?"

Proponents of translational medicine say that the need for it is only getting more critical. "Moving really good ideas into the clinic — now more so than ever before I think we're able to do that more quickly," says Gregory Tsongalis, director of molecular pathology and translational visionary at the Dartmouth-Hitchcock Medical Center. "But the need is so much greater now with the understandings of disease" that have been enabled by genomics, proteomics, and the rest of the systems biology disciplines.

For public-sector scientists, translational medicine means paying attention to the clinical applications of research even during the basic stages. Whether you're working on a particular human gene or a genetic disease, chances are now good that at some point you'll find yourself working with clinicians or at least collaborating with more clinically focused scientists to get your research into a setting where it can have an impact on patients.

In pharma, translational medicine has had a transformative effect on the structure of many organizations, where it functions to connect the previously isolated clinical folks from their discovery brethren. Information that used to flow from discovery to development to the clinic is now looped so that scientists at the bench are working with data gleaned from clinical trials. If it works, it will mean better biological understanding of compounds and their adverse effects, and it could eventually lead to a shortened timeline between discovery and getting a pill on the shelf.

The concept has gotten enough buy-in from people that the US National Institutes of Health have begun tossing buckets of money at scientists willing to work on translational medicine. The CTSA, or Clinical and Translational Science Award, program is one such example. NIH awarded nearly $120 million to CTSA grantees in fiscal 2006, its inaugural year. NIH "felt it was time that clinical research was strengthened as a discipline," says Anthony Hayward, director of the division for clinical research resources for the National Center for Research Resources, which issued the awards. From the outpouring of applications, it was clear to Hayward that "the academic health research institutions were I think themselves frustrated by how slow progress was [in getting research to the clinic]."

Short on People, Not on Problems

In fact, there are plenty of frustrations in getting this field up and running. One primary concern is the "tremendous shortage" of people qualified to do this kind of half-research, half-clinical science, says Leon. A scientist engaged in translational research "needs to have a very comprehensive view of the problem from a technical perspective, from a scientific perspective, and from a clinical perspective," Leon says.

"There is a need for people who can bridge [the basic and clinical worlds]," says Wayne Grody, who runs both research and clinical labs at UCLA. "The two are really fusing. … The downside is there's so much to know — it's become almost impossible to excel at both. While we like to have these physician-researchers, it's been tough going for them recently." The need for new kinds of education has led to the launch of new programs, such as the reworked PhD programs at a handful of US universities funded with $10 million from the Howard Hughes Medical Institute.

But educating the new folks may be less of a stumbling block than educating the old folks. "A lot of physicians realize that there is a genomic revolution and their basic training when they were in med school did not necessarily prepare them adequately for this," says Jean-Claude Tardif, who directs the research center at the Montreal Heart Institute and has pushed for translational medicine for several years. "You need the buy-in of physicians and patients to start using this," he adds.

Join Your Local Chapter

The buy-in of scientists on the basic side will be just as important. Many scientists would prefer not to have to deal with the hassles and regulations that accompany the clinical environment, and others simply aren't sure how to make the connection.

For starters, Michael Phillips advises scientists looking to get into translational research, find an expert. He says Jean-Claude Tardif's push from the clinical side to reach across to the discovery side has been critical in getting the translational program up and running in Montreal. "You're going to need champions," Phillips says. "Many people are very interested in pushing the way we do therapies. If you could find a collaborative partner, that's the way to do it."

"It's a whole different skill set" on the clinical side, says Dietrich Stephan at the Translational Genomics Research Institute. "You need to turn to people who know what they're doing on the drug development side. … There's nothing wrong with asking for help — there needs to be that handshake in the middle."


Where's a Translator When You Need One?

As Felix Frueh, associate director of genomics at FDA, puts it, if you ask three people what translational medicine means, you'll get at least four definitions. We couldn't have said it better ourselves. Here's how some of the experts we interviewed define it.

"I call it translational research because it's going in the direction from research to clinical medicine," says Wayne Grody at UCLA. "It's not pure basic [research] — you can see without any stretch the clinical application. There's a very direct connection. In very short order, the research that you're doing will become a clinical diagnostic mode or a therapeutic modality."

"We define it in pretty broad terms," says Robert Ruffolo, president of R&D at Wyeth. "Any sort of tool that will help us make decisions in clinical trials."

"At Pfizer it's embedded within the clinical line," says Liam Ratcliffe, Pfizer's senior vice president for global clinical R&D. "It's a truly learning and confirming approach to medicine bridging the lab to the bedside — taking molecules from the discovery laboratory environment and finding out what they do in humans and then … feeding back [to research]."

"The way I view it," says Michael Phillips at Genome Quebec and the Montreal Heart Institute, "is how do you bring things from the laboratory … to the clinic in a way that is useful and informative."

"Anything that came out of basic science that we think we can move into a clinical setting to better patient management," says Gregory Tsongalis, director of molecular pathology at the Dartmouth-Hitchcock Medical Center.

"Translational medicine is basically the translation of scientific innovations into health gain," according to Jorge Leon, pharma veteran and biotech consultant.

"Translational research really is at that crossroads … on one axis, the basic science and clinical sciences as they currently are; on the other axis, the development and implementation of novel drugs, diagnostics, and devices," says Michael Lotze, director of clinical and translational research at the Molecular Medicine Institute at the University of Pittsburgh.


A tale of two labs, and the bridge between

Michael Phillips works in an academic medical institute environment, but he's relying on his background in industry to keep the work in his labs on a level that's ready to hit the clinic.

As director of pharmacogenomics at Genome Quebec and the Montreal Heart Institute, Phillips has two labs: one that's more research oriented, and one that's focused on the clinical setting. "The two aren't necessarily compatible," he says, noting that the idea of integrating these groups would be a major challenge. That's in part due to the kinds of people who work in each lab. In the research and development group, he says, he looks for "out-of-the-box thinking" — someone who could buckle down and find an innovative way to make an assay work. But in the clinical group, Phillips says, "these people need to be much more process-driven. They need to be able to run the same assay the same way whether it's today or next Wednesday or next year."

Phillips works closely with Jean-Claude Tardif, who directs the research center at the Montreal Heart Institute as well as running clinical and preclinical studies. Tardif says that the pharmacogenomics center is a key asset that will help the hospital achieve its goal of integrating "genomics and the way we practice medicine. … If we really want genomics to have an impact, we need to translate what is developed at the bench level … into benefits to patients." Having a pharmacogenomics center at the hospital "is the way to go," Tardif adds.

Phillips' early work has revolved around cardiovascular disease. One particular study involves identifying the genomic determinants of toxicity in lipid-lowering drugs, Tardif says; the goal is to predict which patients would suffer adverse events and use that information to prescribe the best therapeutic or even design better drugs that would avoid these side effects.

Going forward, Phillips' group will be "branching out into oncology, pediatrics, and neuroscience." Part of the beauty of having two labs is being able to work on the cutting-edge platforms needed for research without worrying — at least at the outset — about whether those platforms are appropriate in a clinical setting, Phillips says. "It allows me to develop any kind of content on any kind of platform, from gene expression to proteomics, and translate that back into the clinic." There's still a leap between those, though. "Most platforms that I have in an academic setting are not really amenable to being used in a hospital setting." His labs work under GLP conditions, though, to make sure procedures are done as strictly and robustly as they'll have to be done in the clinic.

"Probably what we see is transferring this technology into something very simple that a med tech could use," says Tardif. "We're not there yet. … We have very sophisticated platforms, and we need that right now, but ultimately we want that to be [simpler]."


At UCLA, research meets clinic in the Orphan Disease Testing Center

He's the superstar you've probably never heard of. Wayne Grody, who co-directs the Diagnostic Molecular Pathology Laboratory at the University of California, Los Angeles, has made a name for himself in the clinical testing field for his expertise with ultra-rare diseases.

Grody started a second clinical lab, the Orphan Disease Testing Center, that builds on the success of his regular pathology lab — including CLIA certification, expertise, and resources — but aims at "diseases where the demand for testing would be too low to justify bringing those tests online in a regular clinical lab," he says. The diseases can be so rare that there's just "a single lab in the whole world that has the gene," Grody adds.

The launch of the orphan disease center was equal parts altruism and practicality. In an age where more and more genes are being successfully linked to diseases both common and rare and where regular consumers can keep abreast of these findings simply by using Google, Grody says that many basic research labs are being contacted by people hoping to be genetically tested for rare diseases. "Most of them do it as a favor," he says. "[But] that's technically a violation of federal law." These labs are not CLIA approved and as such are not supposed to be performing what could be construed as clinical tests.

Grody and his UCLA colleagues hit on the idea for the orphan disease center as a solution to this growing problem. The premise is to use Grody's CLIA license and other forms of clinical approval to have a lab that can legally perform clinical testing services using DNA sequencing. As long as a researcher somewhere has the gene to test for the rare disease, Grody's group is willing to do the test. It's a tidy proposition: research labs that have the gene no longer have to feel pressured to perform illegal testing, yet more people with ultra-rare diseases will be able to get the testing they seek.

So far, Grody says, his lab has not received "a huge amount of test requests." He thinks that's just a matter of awareness of the service in the community. But that will change, he predicts, as more people find themselves in the position of having to deny someone testing or having to perform a test that could cost them their federal funding. "Any basic researcher who works on a human gene or human genetic disease [is] eventually going to come up against this issue," Grody says. "If they were aware of us in this parallel world, I think they would be only too happy to call us."

The first orphan disease his center worked on was congenital adrenal hypoplasia, caused by a mutation in the DAX1 gene. "That got us launched," Grody says. Since then, he and his team have worked on several kinds of rare metabolic disorders, muscular dystrophy, and retinitis pigmentosa, among others. While interest from his fellow researchers climbs slowly, the lab has caught the attention of funding agencies. NIH's Office of Rare Diseases worked with the Centers for Disease Control and Prevention to come up with seed funding for labs like Grody's in the hopes that establishing appropriate channels for this kind of clinical testing will reduce the unapproved test services going on at other research labs. The UCLA lab is one of six to receive funding through this new channel, which requires the demonstration of clinical testing conditions; a collaboration with the research lab that has the gene in question; and a solid relationship with a patient support and education group. The lab's first grant through the program is for argenase deficiency, a urea cycle defect that leads to mental retardation and Grody's own orphan disease of interest. The funding agency's "expectation is that you'll bring on two or three rare tests" that otherwise wouldn't have been on the market, he says.

This transition from basic science to the clinical realm, while uncomfortable to many scientists, has been a characteristic of Grody's career from its inception. "My whole life's always been a combination," says Grody, who pursued his MD/PhD at the Baylor College of Medicine so he could see both sides for himself. Today, he has both a research lab and a clinical lab, and he continues to see patients as well.


Yesterday, found memory gene; today, therapeutics

At the Translational Genomics Research Institute in Phoenix, Ariz., the goal is to bring basic research findings to the clinic — and fast. The two clinically minded centers there, one for diagnostic development and the other for therapeutics, are known as "accelerators."

That matches well with the research community's love affair with all things high-throughput. "What we've built here … is an ability to do this type of holistic molecular scanning between people with a disease and people without the disease," says Dietrich Stephan, who directs the institute's neurogenomics division. "Now we have these technologies where you can sift through the entire genome, all the RNA molecules, and almost all of the protein molecules."

Stephan's own research is in the process of being accelerated. Late last year he published a paper in Science demonstrating, through the use of whole genome association studies, the implication of the Kibra gene in memory performance.

But that was late last year. In the meantime, Stephan and his team verified that Kibra performs the same way across multiple populations, and discovered that the gene was turned on in the hippocampus. Functional imaging of people with the two versions of Kibra showed that "people who had the bad flavor had to work their hippocampus harder than people with the good flavor," he says. Today, "we've identified a series of new drugs that target this pathway that look like they really work in animal models," Stephan adds. "We can almost perfectly restore memory to aged rats relative to their young counterparts."

What ever happened to basic scientists performing basic research? Stephan, a geneticist by training, says it's a whole different way of thinking when you've got clinical utility in mind. "I've been tempted many times to say, ‘Hey, what is Kibra doing in the brain?' I could study that for the rest of my life. … But if your next thought is always, ‘How do I modify this biological pathway to have an effect on the human condition?' … it leads your next step in a different direction," he says. "It's not about the paper."


Pharmas adjust for translational medicine

One of the things that gets people most enthusiastic about translational medicine is the effect it's had on pharma. Many pharmaceutical companies have shaken up their whole structure to add translational medicine departments, groups, or some other organizational revamp.

Robert Ruffolo, president of R&D for Wyeth Pharmaceuticals, has been on the conference circuit stumping for the company's new "learn and confirm" model — this idea that the information flow in discovery and development should be circular rather than the one-way road it's been for years. "Ideally, not only should translational medicine be helping us make decisions in our clinical trials, but what we learn in our clinical trials should feed back into our basic research," Ruffolo says.

"We've been working in the area of translational medicine for quite a long time now," says Ruffolo, who notes that translational medicine was formerly known as "experimental medicine" and began at Wyeth as early as 2000. "We'd been making some progress, but it wasn't as much as we felt it should," he says. So last year the pharma reorganized, allowing for a new group called translational medicine. "Whenever we start a clinical trial, even when we make a recommendation, all teams are required to consider a translational approach to development," Ruffolo says. That doesn't mean they have to go that route, but the goal is to get people regularly thinking about translational medicine and how it can be used.

Beyond the internal restructuring, Wyeth reached out in a collaboration to four universities in Scotland for a major translational medicine initiative. "We felt we needed to do something big and different from other companies," Ruffolo says. "At the end of the day we're going to have to compete with much larger companies such as GlaxoSmith Kline and Pfizer, and we can't possibly invest as much as they can." So Wyeth went for an external solution that would use more resources than it had. In the collaboration — which spans medical universities in Scotland, including Aberdeen, Dundee, Edinburgh, and Glasgow — Wyeth gets not only the benefits of the basic research going on at the academic centers but also the funding awarded to the collaboration from the Scottish government. "Scotland has a pretty good cross-section of diseases that are common in the US and throughout Europe and the rest of the world," Ruffolo says — not to mention a strong database hosted by the country's National Health Service. The universities will work mainly on identifying biomarkers, and Wyeth's contribution will revolve around using those biomarkers in clinical trials.

Wyeth is just one example of the transformation pharmas have effected in the hopes that translational medicine will help solve their pipeline problems. At Pfizer, a newly integrated translational medicine group follows on the heels of experimental medicine and other predecessor terms, dating back 15 years now, says Liam Ratcliffe, senior vice president of clinical R&D. With Pfizer's new look, there are translational medicine people posted in each major therapeutic area.

"We're in the business of testing hypotheses around individual candidates or around mechanisms," Ratcliffe says. The information gleaned from the testing should inform decisions about follow-on candidates, preclinical models, and more, he adds. "A lot of translational medicine is describing, and measuring, and feeding back those [data]."

Pfizer recently announced a major, five-year collaboration with Scripps Florida. While not specifically a translational medicine deal, the agreement — through which Pfizer pays Scripps $100 million — anticipates that Scripps will focus on the early parts of the discovery process and feed results to Pfizer, which will attempt to take them to the clinic.


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