The Promise of Translational Medicine

Though the term translational medicine carries many varied definitions, the emphasis on patients and human relevancy is clear, as is its growing importance in medical society today.

Largely driven by the decline in novel medicines, translational medicine encompasses a wide range of scientific areas that relate to the translation of medical research into actual practice at the bedside, or in other words, tangible patient therapies.

Of course, the definitions of translational medicine vary depending on the different constituents – whether it be the patient, the physician, the academic community or the commercial sector. “There are many definitions of translational medicine,” Marincola points out. “For the industry it means more how to move a product from the bench to the bedside, to develop a product to the point eventually of licensing. For academia it’s more how you can test new ideas. And of course, for patients, it's how can you immediately access something that may be available at the pre-clinical/early phase clinical level.”

While translational medicine isn’t wildly different from carrying out other methods of biomedical or clinical research, it comes with the difficulties inherent in testing and applying new concepts in the medical field.

As with the introduction of any novel type of scientific research, the people resources and the communication between them is key. “Translational medicine is a way to try to understand what the problems are and how to solve them,” Marincola says. “A major problem in being efficient in this kind of translation is adding people that have experience in doing basic research and bringing that to the clinics. The ability to create an environment that allows people from both sides to communicate is very critical. In fact, the most difficult problem when trying to test ideas efficiently is the communication between the basic scientists and the clinicians.”

Aside from the communication gap, there exist a number of challenges that must be overcome to advance the state of translational medicine. One of the most prominent challenges lies in the current design of pre-clinical studies, which some deem naïve, claiming that they don’t accurately represent human applicability.

Rethinking clinical models

Many attribute the ineffectiveness of pre-clinical and clinical trials as a major hurdle for translational medicine. Often such facets as human relevancy, the selection of hypotheses and sample collection are scrutinized for being insufficient.

“The selection of the model is not necessarily useful many times because you start from an hypothesis that is not likely to be of human relevance because it’s not based on human observations,” Marincola says. “Pre-clinical models are very useful to test hypotheses, but the problem is the hypothesis is not necessarily well-selected to start with. That’s why it’s important to go to the humans and identify relevant questions.”

Marincola also points out that one of the major flaws is the approach to clinical trials, Rather than conducting trials solely to produce better outcomes, the correct approach should be what can be learned from both the successes and failings.

Sample collection is another area of importance requiring more definite human relevance – as the collection of materials at the right time is a crucial component for effective and useful studies. “Sample collection is a problem because it is very rarely done in a perspective and rigorous way, what I call a forensic approach – taking things at the right time in the appropriate way,” Marincola says.

Marincola attributes three main reasons for the lapse in successful sample collection: first, the lack of experienced, educated individuals to extract serious and validated conclusions; second, approaching new trials with the mindset of obtaining a better clinical outcome instead of simply learning something new that can be applied to subsequent trials; and lastly, regulatory hurdles that complicate the ability to do biopsies and study tumors.

Cancer is a prime example of the challenging nature of trials. “Most people will never study the cancer, but will study everything (such as circulating blood cells) but the cancer itself because the latter is difficult to access,” Marincola acknowledges. “There are technologies to do it in a very efficient way that is not that difficult. But most people don’t do it because it’s difficult for regulatory or other practical reasons and so forth, so you might as well not do the study because you’re still not going to get the necessary information.”

Biomarkers, in particular, suffer from the major hurdles around sample collection, though the hurdles vary depending on the type of biomarker. For example, biomarkers predictive of response will be easier to identify than surrogate end-point biomarkers, which naturally are more complicated and require lengthier time periods for predicting chronic diseases. While technology has demonstrated nearly unlimited potential for advancing the field of biomarkers, poor sample collection still serves as a prominent setback.

“Biomarker discovery is technology-driven; the potential of technology now is almost unlimited, but the problem has always been having material worth studying that is not collected poorly,” Marincola says. “Not having proper information or being able to put it out at the right time is a real limitation.”

Call for collaboration

One major part of the solution to progress translational medicine is improved collaboration between academia and the commercial sector, which would present a significant opportunity to cross-leverage expertise and resources.

“If there was a paradigm shift in academia in which we focus on collaborating with the commercial sector, big universities as well as the NIH could start developing centers of excellence for biomarkers and discovery where you have unlimited resources to do that which biotechs cannot do – and do it in a way that is feasible and cost-effective,” Marincola envisions.

Such a mutual type of exchange would serve as a win-win arrangement for both sectors and would be an important step for the industry overall. The recent backdrop of dried-up federal funding, which has hindered research efforts at major organizations such as the NIH, has only provided further need to pool resources among academia and biotechs.

While the drop in funding poses a large challenge for the academic community – requiring institutions to be smarter and more effective with their resources, biotechs fall at the other end of the spectrum – with plenty of monetary resources but lacking efficiency with their spending. Together, academia would be able to retrieve samples for further study and scientific papers, while biotechs could take part in material transfers and sharing intellectual property.

So how to move forward with the sensitive task of converging materials and intellectual rights? “One way to help develop this collaboration is the relationship between principal investigators and small biotech companies,” Marincola recommends. “Those I find to be very feasible and fruitful most of the way and they’re simply based on one thing: trust. If you can have an exchange based on trust, that’s the only thing that really matters. A trustful relationship is most likely to occur between investigators and small biotech companies because of their direct relationship with the decision makers.”

Pairing the complementary strengths of each other would also serve to broaden the knowledge base and resource pool – with academia providing a much broader view of assays and so forth, while the commercial sector would help in providing the necessary instrumentations and facilities to do more efficient testing.

“This partnership between the commercial sector and academia is incredibly important and has to be fostered by universities or the government where academia can provide intellectual support,” Marincola says. “The intellectual component of the commercial setting is very specialized. Most of the time they don't have the broad picture of many things related to what they're doing. Because a lot of people are very focused on one thing and developing a product, many times they're missing what's going on in the big picture.”

Potential of technology

While clinical trial designs and collaboration are areas indicative of needing improvement, technology has served as a constant proponent of progression.

The rapid evolution of technology has opened many doors in the scientific world, particularly in the arena of genetics where the mapping of the human genome and the development of technologies capable of analyzing subtle genetic differences have helped move the industry closer to personalized medicine and individually tailored therapies.

In particular, microarray technology or gene expression profiling has drastically altered clinical studies. “My bias is that the microarray technology is the one that has done most to advance the field of biomarkers,” Marincola says. “RNA technology/gene expression profiling has been amazing for system biology because you can cover the whole genome; in humans you can use very small samples obtainable with non-invasive biopsies, you can amplify the RNA which allows their utilization of studies at the genome level.”

The profound accuracy of the technology comes from the ability to study RNA to see what the cell is responding to at any given moment. As a result, Marincola views RNA as the most successful technology so far, and looks forward to leveraging some of the new and emerging technology.

“So far the RNA technology looking for gene expression is the most comprehensive and reproducible, but they're improving other technologies, like DNA technologies, to look at the whole genome variation in a single chip,” Marincola remarks. “There are new technologies coming out that offer ways in which you can actually in a single chip study the whole genome right away which is pretty impressive.”

Because the influence of genetic background plays such a critical factor in the causes and outcomes of disease, being able to look at both the tumor and the genetic makeup is crucial as the scientific community moves forward.

“This combined approach is very important and the technology is growing,” Marincola says. “For example, now you can actually prepare chips where you look at the whole genome variation in a person. At the proteome level, I think there's still much to go because the technology is not at the point that can provide that kind of discrimination.”

About Dr. Francesco Marincola

Dr. Marincola is Chief of the Infectious Disease and Immunogenetics Section in the Department of Transfusion Medicine at the Clinical Center of the National Institutes of Heath in Bethesda, Maryland. Marincola received his MD, cum laude from the University of Milan, and his surgery training at Stanford University where he also completed a postdoctoral fellowship in surgical research. He joined the Surgical Oncology Branch of the National Cancer Institute, NIH, in 1990. Marincola serves as the Editor in Chief, Journal of Translational Medicine.

Ins and outs of translational medicine

Translational medicine increases the efficiency of determining the relevance to human disease of novel discoveries in the biological sciences, and helps in the identification of alternative hypotheses.

Translation medicine aims to improve therapeutic outcomes by:

• Validating the clinical potential of novel discoveries
• Identifying novel concepts relevant to human disease
• Increasing the efficiency in which new therapeutic strategies can be tested on human subjects
• Providing feedback to researchers about the effects of treatment
• Developing reagents for the characterization of disease processes

The need for translational efforts rests on three main premises:

• The need to find cost-effective solutions to chronic medical conditions
• The need to efficiently test novel diagnostic and therapeutic opportunities