Translational Science: Bridging the Gap

Diagram of arteriole and cells

Diagram of arteriole and cells

Scientific discoveries typically begin at the bench, with basic research through the study of diseases at a molecular or cellular level, then progress to the clinical level, or the patient’s bedside. Scientists are increasingly aware that this bench-to-bedside approach to translational research is actually a two-way street. Basic scientists provide clinicians with new tools for use in patients and for assessment of their impact, while clinical researchers make novel observations about the nature and progression of disease and gather biospecimens that are necessary to fuel the next generation of basic investigations.

The growing complexity of cancer research requires collaboration among professionals with highly diverse skills and training, as well as a team approach to scientific inquiry, in order to develop clinically useful drugs and devices. The conception, pre-clinical testing, and clinical evaluation of a diagnostic or intervention (i.e., preventive or therapeutic) approach often demands concerted interaction between investigators with diverse backgrounds, across traditional disciplinary boundaries.

To find out more about the acceleration of progress through translational research, BenchMarks spoke to Ernest Hawk, M.D., M.P.H, director of the Office of Centers, Training and Resources. Hawk oversees cancer centers, cancer training programs, and a national initiative intended to expedite foundational scientific discoveries into meaningful clinical tools to prevent and treat cancer, through programs such as the Specialized Programs of Research Excellence, as well as providing leadership to the Translational Research Working Group (TRWG).

How would you define translational research?

Translational research encompasses all of the processes needed to develop promising basic laboratory and epidemiologic discoveries into new cancer-related drugs and biologics, medical devices, and behavioral interventions that benefit people living with, or at risk for, cancer. Such development depends on creating effective links between basic, clinical, and population scientists.

Give us an example of how translational research has worked in creating new therapies.

Here are two examples of discoveries arising from lab- or population-based investigations that were subsequently developed into useful clinical products − in these cases, agents that prevent or treat cancer. The first is Gleevec (imatinib mesylate), which resulted from the discovery 45 years ago of the Philadelphia chromosome in patients with chronic myelogenous leukemia (CML). Subsequently, researchers carried that chromosomal observation to the molecular level, discovering that it results from a translocation of the Abelson oncogene to a ‘bad’ region on the nearby chromosome, termed the breakpoint cluster region (BCR). That translocation results in an abnormal tyrosine kinase protein that causes CML, a disorder in blood cell development. Researchers were then able to transform that insight into a drug that effectively inhibits the altered protein – Gleevec. In this case, it took decades to translate the biologic insights into an effective drug, achieving two significant breakthroughs. First, Gleevec is now a marketed drug that offers hope to many people living with CML by prolonging their lives. Second and more broadly, it laid an important conceptual foundation for future progress against cancer.

Another example is the discovery of the role that prostaglandins play in cancer development. In the 1970s and 1980s, scientists recognized through animal and population-based studies that an enzyme called cyclooxygenase (COX) was important in the body’s inflammatory response, and in the development of pre-cancerous and cancerous tissues. Complementary observations in both the lab and the population enabled scientists to understand the roles of cyclooxygenases (and some of their products, prostaglandins) in cancer development and to test them in the clinic relatively quickly. These clinical investigations proved that drugs like aspirin or celecoxib (i.e., non-steroidal anti-inflammatory drugs or NSAIDS) indeed inhibit the development of intestinal neoplasms in certain patients.

Does translational science include prevention strategies or screening devices?

In addition to therapeutic drug development, translational science encompasses many other promising approaches to reduce cancer incidence, morbidity and mortality. Moreover, translational science relates to at least five developmental strategies relevant to cancer prevention and/or treatment: 1) risk devices that better predict cancer development or outcomes at any stage of disease (e.g., a molecular test or new device that can be used for improved cancer screening, early detection, diagnosis, or prognosis); 2) interventive agents (i.e., new drugs to prevent or treat cancer); 3) biologics and vaccines; 4) interventive devices (i.e., new instruments such as photodynamic devices or cryotherapy probes to prevent or treat cancer); and 5) lifestyle alterations (e.g., changes in tobacco use, diet, physical activity to prevent or treat cancer).

Why is there a need for more attention to translational science now?

There is growing scientific opportunity because of our increased understanding of carcinogenesis, but there are many challenges, as well. For example, the growing complexity of cancer-related research requires “team science,” an approach that demands substantive collaborations among professionals with diverse skills and training, such as biologists, engineers and even computer programmers. Increasingly, scientists must work in interdisciplinary teams to understand and fully explore the interplay among environmental, lifestyle, genetic, and molecular factors that contribute to cancer development.

What is NCI doing to translate basic research findings into new tests and interventions that might help people who have cancer or are at risk of developing cancer?

The NCI has a rich portfolio of programs and investigator-initiated projects in translational science. Indeed, many of these either arose or grew substantially over the last decade, as translational opportunities became more compelling. The TRWG was established to evaluate the status of NCI’s intramural and extramural investment in translational research, and to envision its future. It will attempt to do so in an inclusive, transparent, and reasonably comprehensive manner, by involving broad community input, inviting public comment, and recommending ways to better coordinate research activities across the institute. Its ultimate aim is to accelerate progress by ensuring that all components of our translational investments jointly advance science toward our goal to improve the health of the nation and its cancer patients.

How do you link research in the lab, the clinic, and the population more effectively?

That’s the essence of the TRWG—answering this question and then suggesting how to implement the solution. Of course, there’s already a lot going on in this regard across the spectrum of NCI’s programs. A prime example is the Early Detection Research Network (EDRN), which brings together dozens of institutions to accelerate the translation of new biomarker discoveries into clinical applications intended to identify cancer earlier, and to quantify patient’s risks more effectively and efficiently.

How can translational research be more effective, and what types of facilities and technologies are needed?

In most instances, translational research necessitates a multidisciplinary approach that involves scientists in the lab, clinic, and population working together productively. Given this premise, coordination and communication are clearly critical parts of effective translational research.

As far as the types of facilities and technologies that are needed, translational science certainly benefits from a strong, stable infrastructure; in many instances, the NCI-designated cancer center support grant provides this foundation. Cancer centers often provide funds for a variety of shared resources that are useful in translation—such as genomics, proteomics and biostatistics cores. Another thing that’s required is a dedicated process that prioritizes competing scientific projects. Again, cancer centers typically provide this service through protocol review and monitoring systems. Finally, translational science requires standardized terminologies and data collection methods, a critical need that is addressed by caBIG ™ (i.e., the cancer Biomedical Informatics Grid ™) platform, which connects disparate Web-based programs within − and ultimately across − NCI-designated cancer centers.

What types of training programs need to be developed to train the next generation of translational researchers?

NCI has a large portfolio of training programs, many of which are actively developing the next generation of translational scientists. These programs give basic scientists an appreciation of clinical science through various educational programs, and offer clinicians an opportunity to explore basic science investigations in laboratory settings, thereby enhancing researchers’ fluency in the language of basic or clinical science.

Extending our consideration to population scientists, we have dedicated training programs for this discipline, as well. The challenge moving forward is how to reinforce the notion of so-called “team science,” or multidisciplinary science to and through investigator training and re-training. The growing reality is that it is rare for a single individual to be capable of performing adequately in all of these domains as a sole investigator at all stages of his/her career.

Does recruitment for clinical trials need to change when you’re talking about translational research?

Translational studies by their very nature can be somewhat more demanding of investigators and participants than traditional trials focused on clinical endpoints. For example, translational trials typically involve the collection of biospecimens to provide insights into the mechanisms of an agent that can be used as an intervention, or into cancer itself, on cellular and/or molecular levels. Occasionally, they require serial sampling, as well. Both of these activities require more from participants than traditional trials do, but they also lend for tremendous scientific insights, as well. Indeed, some have characterized the notion of translational trials as, “…doing smaller trials but getting more knowledge out of each encounter.” Given the modest levels of patient participation in current clinical research, the most critical issue may be one of education – for potential investigators, as well as participants. Clinical research involves excellent care – at least, concordant with standards of care – along with the opportunity to gain additional benefits, while simultaneously contributing to future improvements.

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