In a departure from its traditional support for clinical investigators with a basic research interest, the Howard Hughes Medical Institute (HHMI) has announced a new initiative to fund the work of 12 of America's best physician-scientists in an effort to harness new opportunities in translational research.

With such generous funding on offer—$1 million annually for each investigator over five years, plus payments to the host institutions for laboratory space—the program bears scrutiny. Is the research being funded truly translational in that it will move basic research findings to patients? Or will the program simply extend HHMI's already excellent support of its 324 other investigators interested in human disease research without any immediate clinical benefit?

Much relies on the definition of what is a translational researcher. Lee Nadler is senior vice president for Experimental Medicine at the Dana Farber Cancer Institute in Boston, and is charged with promoting the translation of basic research discoveries into clinical applications. He maintains, “A translational researcher is someone who takes something from basic research to a patient and measures an endpoint in a patient.” And he believes that this description applies to only a few of the new HHMI physician-scientist investigators.

A list of the new HHMI investigators and their research projects can be seen at http://www.hhmi.org/news/052802.html.

Nadler was invited to give the Seventh Joseph H. Burchenal Clinical Research Award Lecture at the American Association of Cancer Research in San Francisco this April. He caused consternation among the audience who had expected to hear a scientific lecture and instead received a warning that physician-scientists would “go the way of the dinosaur” if the community did not invest more seriously in translational research. He outlined the divide between translational researchers and biomedical scientists (Slide 1).

“I'm supposed to be the example of the translational professor,” Nadler told Nature Medicine. “I have a Burroughs Wellcome award and also a Ludwig professorship, but I'm telling you we can't train the next generation because there is now an enormous amount of science to bring to patients and no one to do it. The Hughes is only filling a small niche.”

A dozen of the best: K. High, E. Mignot, B. Lee, C. Sawyers, R. Darnell, B. Walker, H. Hobbs, T. Golub, R. Siliciano, E. Stone, C. Walsh, B. Druker.

Charles Sawyers of the David Geffen School of Medicine is one of the new HHMI investigators. “According to Lee's definition, I am measuring signal transduction pathway endpoints in patients' tumor cells,” he says. Sawyers' project focuses on the tumor-suppressor gene PTEN, which is deleted in a subset of patients with glioblastoma and prostate cancer. PTEN encodes a phosphatase that regulates the PI3 kinase/Akt signaling pathway. “In the lab, we showed that the drug rapamycin, and a derivative called CCI-779, works well against PTEN-null tumors because it inhibits mTOR, a kinase in the PI3-kinase/Akt pathway. The next step is to test this in patients whose tumors have PTEN mutations and to do this, we need to develop assays to recognize PTEN-null,” says Sawyers.

The project is a beautiful example of translational research—one that characterizes the molecular mechanism underlying a pathology in the laboratory, determines a way to measure this in the human disease state in situ and develops a beneficial intervention in the clinic.

Sawyers is experienced in such research. Together with Brian Druker at Oregon Health & Science University—also a recipient of the new HHMI funding—Sawyers was responsible for bringing Novartis' medicine, Gleevec (STI571), to the market for the treatment of chronic myeloid leukemia (CML). Gleevec specifically inhibits ABL1 protein tyrosine kinase, which is constitutively 'on' due to a chromosome translocation in CML, activating a number of signal transduction pathways involved in cell proliferation and apoptosis, leading to myeloid proliferation.

“The Gleevec trials began as a small project sponsored by Novartis, but done essentially as investigator-initiated work,” says Sawyers. He describes the process of repeating the bench experiment in patients: “The laboratory science done on patient material was a critical part of the translational science, measuring BCR-ABL kinase activity in patients during response and at relapse. These molecular endpoints are what need to be measured in all trials with targeted agents. A translational researcher needs to figure out how to do this. It was pretty easy in CML because of easy access to tumor tissue, the homogenous disease state etceteras. But it will be much harder in solid tumors.”

Nadler further advises that translational research is based around teams rather than individuals (Slide 2). “Virtually nobody is attempting to create the necessary middle [infrastructure] that takes work from the lab to the clinic,” he says.

Here again, Sawyers provides a model example in how he plans to spend the HHMI money. “Developing molecular endpoint assays in clinical material requires expertise in pathology and molecular biology, and the use of those assays in clinical trials. This is a team approach needing collaborative interaction between clinical and laboratory individuals who often do not speak the same science language,” he says.