Defining translational medicine isn't easy. According to some experts, the term has almost as many definitions as practitioners. "It reminds me of the story about the blind men and elephant; people tend to define translation as their part of drug development," Edward Spack of SRI International joked in the "Career Advice" section of Science magazine several years ago. "Speak to anybody from any company or academic institution and they'll have a new focus on it and a host of names," observed Trevor Mundel of Novartis in the same article. Indeed, the field is so huge, the American Association for the Advancement of Science (AAAS) now has an entire journal devoted to translational medicine.
To further complicate the picture, a new buzzword recently emerged—convergence—to describe the integrated approach to research that translational medicine seems to require. The authors of a recent Massachusetts Institute of Technology white paper aimed at the health science research community define convergence as "an important new research model…which draws on an ongoing merger of life, physical and engineering sciences." They see convergence "as a blueprint for innovation," a "revolution" and, of course, a "paradigm shift."
Regardless of what it's called, this merging of technologies and disciplines has specific consequences and implications in the context of SLAS. For this article, SLAS leaders and members weighed in on the paradigm shift and its impact on their current and future work.
To SLAS members Robert Hertzberg and Ricardo Macarron, both of Glaxo SmithKline, translational medicine means "introducing greater predictive power in our early drug-discovery work so that molecules and knowledge translate well—in terms of both efficacy and safety—as we move from in vitro and animal models into humans."
SLAS member David Dunn of Hurel Corporation adds that for translational medicine to succeed, "we need to think outside the discovery sandbox and integrate the clinical perspective into everything we do, right from the outset."
According to the MIT white paper, the convergence model requires "not simply collaboration between disciplines, but true disciplinary integration." In this regard, academia seems to be leading the way.
"Academics tend to cross boundaries more easily than people industry; it's in their nature," says SLAS President Michelle Palmer of MIT and Harvard's Broad Institute. "Many new initiatives in academia are being formulated around bringing together cross-disciplinary expertise." Examples reported in a recent Scientific American article include New York University's new Biomedical Chemistry Institute, where chemists and biomedical researchers share laboratories and collaborate on new drugs and diagnostics; Columbia University's Northwest Corner Building, where biologists, physicists, engineers and chemists work in open-format labs; and MIT's new David J. Koch Institute for Integrative Cancer Research, where biology and engineering labs share common space and features.
"The U.S. government is creating a number of funding mechanisms to facilitate cross-fertilization," Palmer observes. Examples include the Therapeutics for Rare and Neglected Diseases (TRND) program, various National Cancer Institute initiatives and the still-evolving National Center for Advancing Translational Science (NCATS). "SLAS is uniquely poised to provide relevant forums and encourage important interdisciplinary connections and collaborations," Palmer says.
On the industry side, companies also are starting to implement processes consistent with convergence/translational medicine. Clinical biomarkers is an area that is receiving a good deal of attention in that regard, according to Dunn. An example is the clinical biomarkers group at Bristol Myers Squibb, which "straddles the discovery group and the clinic," he says.
"The group is responsible for taking biomarkers from discovery and translating them into methodologies that then can be transferred to the clinic. Then there has to be communication from the clinic all the way back through discovery. So you have multiple stakeholders and multiple voices in the discovery and development of a new drug," he explains.
"When you have multiple stakeholders driving these programs, there's no longer a simple handoff from one department to another, where one person does his piece and the next person does his. There's a more open, active dialog among everyone concerned, many of whom are viewing the drug-discovery process from completely different perspectives."
For that kind of dialog to be effective, everyone involved has to be able to communicate effectively, Dunn stresses. When he was at Wyeth, "we worked on a project that was a good example of a translational medicine in action," he recalls. "We linked up with the development group that was investigating genetic markers that conferred resistance to a breast cancer drug. They approached the discovery group to help them do an RNAi screen that would identify those potential genes. There was no friction between the groups. Everybody was excited about the discovery-development project, and everybody saw the benefit of it."
That might not always be the case, he acknowledges. "The demands placed on people in the clinic are different from the demands placed on the people in discovery. In the clinic, there's much more at stake, the impact of failure is much higher, and timelines are more rigid." Dunn described a scenario in which a biomarker potentially predictive of a response to a drug is under investigation at the same time that the drug is in the late phase of a Phase II trial.
"The development team will to want to start integrating that biomarker into the clinical study. But before they can do so, the discovery team has to do a lot of work to bring that biomarker to the point where it can be validated and utilized," Dunn says. "This means there's an urgent need in the clinic, and a complex scientific task with a good deal of uncertainty that has to be done in discovery." To avoid pressure and conflicts, "there needs to be transparency, so each group knows what the other is up against. There can't be a situation where the clinical person shows up at the door and says ‘Next month we're going to start this trial. How's that biomarker you're working on?'"
A corporate structure that supports and connects these groups is key, adds Macarron. "Many large companies need both the small groups that focus on specific therapeutic areas, and the bigger groups that provide the platforms necessary to bring the results to scale. So there needs to be a way to coordinate disparate groups and technologies for translational medicine to really be successful."
If some of this sounds familiar, well—it is. The Scientific American article asks, "Is ‘convergence' a revolution in science or jargon?" The author observes that the "concept of merging tools and methods from separate disciplines is not new," noting that the sequencing of the human genome "spawned integrated fields such as bioinformatics and systems biology."
Macarron acknowledges that translational medicine is, in a way, "a repackaging of the personalized medicine idea that's been around for at least 20 years." Hertzberg agrees that "it's just a new term for something we've been doing for a long time." However, that work is poised to bear fruit more quickly. "What's really different now," says Hertzberg, "is that we have new and emerging technologies that make it more feasible to create and take advantage of these connections between the clinic and the lab."
Yet, these same capabilities are also creating obstacles. "Getting to the point where we're giving the right medicine to the right patient in a rapid, targeted way involves more work for pharmaceutical research overall," Macarron says. "Whereas before we had an okay substance for many patients, now we have to produce the perfect solution for every patient, and every one is different. That's a major barrier."
"What it means," adds Hertzberg, "is that companies are paying more to do clinical trials and ending up with smaller markets. On the positive side, you end up with a much more efficacious and safe drug for the market, and you have a potentially higher success rate because you're targeting the patients who can benefit the most. But in the short term at least, you have to invest more in getting less."
Whether that investment bears fruit hinges largely on genetic sequencing technologies (a topic that will be covered in greater detail in an upcoming issue of this publication), which will pinpoint patients most likely to respond to a particular candidate drug. An example is GSK's investigational agents, GSK2118436 and GSK1120212, which are being tested in two global Phase III studies in patients with advanced or metastatic melanoma who have a BRAF V600 mutation. The studies will separately assess the efficacy and safety of the agents to determine their ability to stop or slow the progression of skin cancer in patients whose tumors contain the mutation, which occurs in 50% to 60% of melanoma patients. "This is an example of our taking observations from the clinic, translating them back to observations from the lab about our molecule, and then modifying our clinical trials to target the right population," Hertzberg explains. Roche also is testing an investigational melanoma agent targeted against the BRAF V600 mutation, and other companies have similar programs in the works.
Nonetheless, even if the personalized treatment works, that does not mean it will move effortlessly into use in the targeted treatment group, according to Macarron. As with herceptin, another cancer drug created for a specific market (women who are HER2-positive), any new agent would require a companion diagnostic tool to make sure the drug is given only to those who could benefit. "One obstacle is who pays for the diagnostic part? There's an extra cost to the healthcare system to determine who is the right patient for the drug," he says. "Over the long term, it's less expensive, because you're not giving a drug to the more than 50% of patients who won't respond to it. But in the short term, it's more expensive."
Looking ahead, emerging stem cell technologies are pushing translational/personalized medicine to the point where it's becoming easier to envision targeting therapy to individuals, Hertzberg observes. "Using induced pluripotent stem cells, it's now possible to take a cell from a single patient, and create an assay from that cell that works in vitro. That's a kind of single-patient, single-assay translation. One day, we might be able to create an organ in a dish from a patient. That would be translational medicine on a real patient-specific level."
If translational medicine is the wave of the present and future, what do SLAS members need to know to get hired and make their mark in the field? "An attractive candidate for working in the area of translational medicine is someone who has breadth," Hertzberg says. "An example is a physician who also knows about basic research and has worked at the bench. Or, if you're not a physician, at least if you have knowledge of both the clinical and non-clinical sides, that would be helpful. The bottom line is that a much broader knowledge base is needed than what was required in the past, where a scientist could focus narrowly on a single field."
To acquire that "breadth," Hertzberg recommends moving around different parts of an organization instead of staying in a single niche. Working in one of the newer centers described at the beginning of this article, which combine comprehensive clinical centers and basic research in a single setting, can also provide a more rounded experience. SLAS conferences, global symposia and resources posted at SLAS.org can also help readers gain knowledge and make connections to move their careers forward.
August 1, 2011