Aditi Bhattacharya gives a flavour of the different ingredients that help to successfully carry over ones research findings from the lab bench to the patients’ bedsides.
In between long hours of coaxing finicky mice to ‘behave’, I spent many days last summer avidly following the Rotavac vaccine story. While the press coverage was undeniably deserved for the successful results in the clinical trials, the story started long back, in the 1980s, with thousands of hours of research in India and US. Rotavac can be considered a thumping endorsement for translational research and ‘India Shining’. World over, significant time, effort and resources are being devoted to what is broadly called translational research. Translational research is nothing new and previously existed silently under the alias of applied research. Now, the lines between basic and applied research are getting blurred and what was once a linear relationship more has now evolved into a circular one.
Translational science is the process by which basic research findings are transformed into viable and usable applications for improving health or solving other ecological and biological problems. While we celebrate the triumphs of a handful of success stories, there are a lot of failures and unfinished work, so one should consider the investment, limits and timescales involved before going down this road. To do that we need to understand what translational research is, how one goes about it, the challenges and payoffs, and most importantly how excited we should be by the high volumes of related research being published in major journals these days. Being engaged in it to some degree, I think of it usually as a multi-dimensional relay race with lots of hits and misses. While a lot is written on the trials and tribulations of human clinical testing, I’d like to focus on the stage in which the baton is still firmly outside human arena. Consider this a generalized ‘how to’ guide on embarking, conducting and presenting translational work as a bench warrior before handing it over to the experts in industry. There is no one superhit formula and the approaches should be tailored to the needs of each situation.
We have come a long way from just relying on serendipity to discover our next drugs and instead build on years of work to understand a disease process. So, one of the starting points of a typical translational medicine story could just be the next interesting finding from your cell culture or in vitro experiment. At this stage, hypothesis and proof of concept are firmly in the arena of basic research. The idea is speculative and requires a lot of evidence to validate. At this point it is prudent to consider how you want to proceed with developing therapeutics based on this exciting new concept. For instance, if your previous study relies on modulating gene expression at the level of DNA, broad spectrum HDAC inhibitors may be great to prove the concept, but they are not suitable for therapy in human beings.
The lack of viable experimental agents that recapitulate your basic research is a major stalling point. The choice of the agent is critical since it has to be something that is specific enough to engage the cellular process you want to target, yet be amenable enough to be given to a whole animal via intra-peritoneal, oral or other routes. The other questions to consider can range from — will it be a small chemical molecule or a DNA based therapy? Does it need a delivery agent like nanoparticles? Are the compounds available or need to be invented? This search can be surprisingly short or may need many years; but once you have zeroed in on the potential candidate, another set of challenges set in — for example, the approach that worked in a cell culture dish may need some modifications to pass beyond the liver or blood brain barrier in a whole organism. Many compounds are given directly to site of action in the body, but one needs to evaluate toxicity upon spreading, tolerance over time etc. Hence, pre-clinical validation is an intense process and is a delicate mix of pharmacokinetics, biochemistry and whole organism assays. Finally, you must also consider what experiments you will conduct on the whole animal to test your candidate therapeutic. For example, for cancers the metric usually is decrease in tumor size or related parameters, however for neurologic diseases, picking the right behavioral tests to test your candidate molecule is critical.
In parallel, before embarking on the project, it is worthwhile for the researcher to spend some time understanding the disease not in its biological avatar, but its clinical face and the life of a person with the condition. This gives a fresh perspective, and brings home the responsibility of finding a therapy. It also helps design your pre-clinical validation experiments. For example, spending two hours a week in a clinic with patients with disease ‘A’ may help you decide that a therapy may well be worthwhile if it rescues epilepsy associated with the condition rather all the symptoms at one go. Across the world, numerous fellowships, meetings and workshops are being conducted to enable bench-experienced scientists to get exposure to clinic-based doctors and patients to talk and work together to find a solution.
The other major shift that a bench-based scientist needs to appreciate is that the performance of a chemical agent will likely have off-target side effects that have to be documented and reported. This is not something we bench warriors are comfortable doing, largely because there is no incentive to do so when publishing manuscripts in mainstream journals, where usually, only the perfect story is rewarded. However, given the complexity of the whole body, it is unlikely that your candidate therapy will be ideal in every way. This need is being increasingly addressed in specialized translational journals like Science Translational Medicine, Journal of Translational Medicine, Clinical and Translational Science where reports of adverse events and how they were managed are being encouraged and published. So researchers would better serve their science and the disease community by considering where they publish their findings. One also hopes that the review process in mainstream journals becomes increasingly open to sharing and discussing negative results.
Safeguarding your intellectual property before handing over the baton to experts that herd in the next stage is also important. While some PIs opt to start companies that will develop the compound further with external funding, others choose to tie up with a consortium made up of doctors and pharma support. The final phase is dealing with the publicity of a well worked out project that has culminated in a good publication. Usually press releases from the university or institute are cautious, and present the study in the most realistic light. Popular press has the duty to report findings realistically and not sensationalize a finding to make it news worthy.
Do things work differently in India? As with most things, translational research in India has recently got much encouragement and support. Hopefully we should have takers for all these opportunities and should see results in due course. At the academia end, two new biotech clusters have emerged — NCR and Bangalore. Institutes like Translational Health Science Institute, Institute for Molecular Medicine, Tata Translational Research Center, InStem and C-CAMP have been set up. Simultaneously, new grants (Wellcome-DBT Indian Alliance, BIRAC-Wellcome joint-call for translational medicine and other grand challenges initiatives funded by overseas foundations) are being made available. Most, if not all international organizations, committed to curing a certain disease, do not limit their support to specific countries.
However, most of these initiatives are at the end of getting basic research transformed into a potentially usable treatment modality. There are sizable roadblocks at the end of getting the said modality delivered in usable form to practicing physicians. A good discussion of the India-specific problems can be found at this freely accessible speech by Dr. Kiran Mazumdar, Biocon. Problems also exist in the business model of Indian pharma companies that focus largely on producing generic drugs. The upcoming biotech sector, is attempting to foray into more high-risk-high-gain arena, but they also face problems in securing funding, getting multi-tiered governmental approvals, and finally, the lack of proper framework to conduct early stage clinical trials. While many clinicians were previously content to conduct trials for foreign companies, recent IP issues and withdrawal of many funded trials is slowly forcing them to look inwards for innovation-driven research and therapy. We are in a state of flux, and the coming years will be critical in deciding how we overcome existing problems and utilize the opportunities. For now, translative work is well funded and supported on the bench-to-candidate therapy side; but for it to complete the journey to the patients’ bedside, we need additional infrastructure to kick in. But if you, like me, are doing the trapeze act from the bench side end of things, the scenario is bright and exciting.