After completing his PhD coursework at the University of California, Los Angeles, Neil Shah could readily recite the molecular biological underpinnings of chronic myelogenous leukaemia (CML). But it was only after following a haematology–oncology clinician on rounds and meeting a CML patient that he felt he understood the disease.
"It put a human face to what I understood at the molecular level," says Shah of his literally bench-to-bedside training. Shah, now a clinical investigator at the Los Angeles campus, uses that mixed 'translational' background to study the mechanisms by which some leukaemic cells become resistant to some chemotherapy drugs, in an attempt to develop ways to override that resistance.
Irwin Arias: demystifying medicine for PhDs.
During the past few years, government agencies, universities and private foundations — such as the Leukemia and Lymphoma Society, which funds Shah — have been steadily pushing for more such translational research (see 'Foundation funding'). These programmes mean that the number of opportunities is increasing for scientists who are willing to undergo a longer training period in order to grasp both basic and clinical research.
Irwin Arias — assistant to the director of the Office of Intramural Research at the National Institutes of Health, and professor of physiology and medicine at Tufts University School of Medicine in Boston — says that the clinical setting is becoming a popular occupational route for PhDs, in addition to MDs doing basic-science postdocs, and notes that the demand for MD/PhDs has been high. Arias has long held an interest in translational medical education: he started a course at Tufts in the 1980s to train PhD students, fellows and faculty members in pathophysiology. He most recently created and directs a course for the National Cancer Institute to demystify medicine for PhDs working there. Other institutes are considering offering similar courses that are specific to their research areas.
MULTIPLE CHOICE
There are several possible paths to a translational career. Some take the bench-to-bedside route, starting out with a PhD in basic research, but then adding clinical experience from fellowships, coursework and collaboration with physicians to bring their ideas to patients. Others go from bedside to bench: 'physician-scientists' — MDs or MD/PhDs who spend their time primarily in the clinic — seek to work more in the lab. Finally, a few, like Shah, come at the issue from both directions while aiming for a specific research niche.
Hayley McDaid took the bench-to-bedside approach. Her interest in translational medical research started with her PhD studies at Queen's University in Belfast, UK, continued as a molecular-oncology instructor at the Albert Einstein College of Medicine in New York, and was facilitated five years ago with a Susan G. Komen Breast Cancer Foundation fellowship.
What helped McDaid along the way was her ability to cultivate research relationships with already-established clinicians. She contacted Sridhar Mani, a physician also at Einstein, to collaborate on a clinical study using the molecules she is investigating.
"This also helps with getting funded," she notes. Her advice is to embark on good relationships with outstanding clinicians for the early phases of translational research. Then build on that by applying for other types of funding, such as the translational-research fellowship from the American Association for Cancer Research and drug firm Amgen that funds her current research.
Another group travels in the other direction, getting medical training first, then becoming more involved in basic research. Italian MD Laura Pasqualucci, now assistant professor of clinical pathology at Columbia University and a Leukemia and Lymphoma Society special fellow, took that path when she moved from Italy to New York six years ago, to improve her molecular-biological skills.
Working in the lab of Riccardo Dalla-Favera, she studies genetic alterations specifically associated with B-cell diffuse large-cell lymphoma and how this might be used to identify new targets for diagnosis and therapy. She notes that, in her experience in Europe, it is easier to get funding for translational medical research than for basic research.
LOST IN TRANSLATION
David Feldman feels that the problem with translational science is that everyone has a different definition of it.
Translational medicine might seem to be rewarding and full of opportunities, but there are a few issues to grapple with for those who span both areas. "The problem with translational science is that everyone has a different definition of it," says David Feldman, an MD/PhD and director of heart failure and cardiac transplantation at Ohio State University in Columbus. This sometimes vague idea of what constitutes translational medical research puts the onus on the grant writer to make sure that both molecular-biologist and clinician reviewers understand the fundamental and applied sides of the proposed project.
Getting funding for translational research can be especially challenging for investigators early in their careers, says Jim Olson, an MD/PhD who is an assistant member at the Fred Hutchinson Cancer Research Center and assistant professor of paediatrics at the University of Washington, Seattle. "If you haven't already translated a drug, reviewers are uncertain that you can do it," he says. Olson is in the first year of his Damon Runyon–Lilly Clinical Investigator Award, seeking new treatments for brain tumours in children.
Many universities are trying to recruit translational investigators, but often their work doesn't fit into the traditional tenure-track model, he says. For example, published studies in the translational area tend to appear under collaborative-group authorship, whereas first-author papers are prized on the tenure track.
Anna Keating: combining basic and clinical science offers several benefits.
Anna Keating, an MD who is a fellow in paediatric haematology and oncology at the Memorial Sloan-Kettering Cancer Center in New York, has not seen collaborative authorship and tenure review as a problem for herself or her colleagues. She is now in the first year of her Leukemia and Lymphoma Society fellowship, testing strategies to enhance the cytolytic activity of donor T cells. She says that translational researchers can benefit from the mix of journals in which they could publish, as their papers can have a basic as well as a clinical slant: basic-science papers can be published first to get the first-author papers out in time for review. "But," she says, "it could also be institution-dependent in whether this is a problem" — depending on whether the departmental faculty members are basic scientists or mainly clinicians.
Despite possible problems in finding a comfortable academic fit for translational research programmes, the field is coming into its own, with bedside observations informing benchtop discoveries and vice versa. This has been the case for Albert Koong, an assistant professor of radiation oncology at Stanford University and a Damon Runyon–Lilly Clinical Investigator Award recipient. He studies pancreatic tumours, which are deficient in oxygen — a condition called hypoxia — and is looking at the signalling pathways during hypoxia with a view towards developing therapies based on that. His field-crossing studies ask why there is such an early propensity for the pancreatic tumour to spread, and whether the molecular biology of hypoxia plays a role in early metastases. His work in the clinic and with clinicians steers the direction of his basic research and helps him to formulate good questions about the nature of pancreatic cancer.
The upshot, says Keating, is that translational research "needs bi-directional communication" — clinicians and basic researchers can help to solve each other's experimental problems.
Web links
Leukemia and Lymphoma Society
http://www.leukemia-lymphoma.org
Susan G. Komen Breast Cancer Foundation
American Association for cancer Research
Damon Runyon-Lilly Clinical Inestigator Award
http://www.cancerresearchfund.org
Wellcome Trust
