Just like the Big Data (or Big Data Analytics), Translational Medicine has been another hot trend in recent times. Translational Medicine (TM) is also known as Translational Science (Research), Evidence Based Research, or Disease Targeted Research.
Translational Medicine is the process of using the findings of laboratory research to develop new diagnostic tools and treatments, and similarly using the research findings from clinic (clinical trials) to develop new research ideas for laboratory research. Translational Medicine is based on three pillars – benchside (laboratory), bedside (clinic/hospital) and community (patient and general public involvement). It is kind of the interface between basic science and clinical medicine. The translation is not unidirectional. Translational happens while applying the knowledge gained through fundamental research in the lab towards new ways to diagnose and treat diseases. It also happens when clinical observations lead to new research issues (questions and ideas). So, bench to bedside, and back to bench. For in-depth understanding, please refer to Translational Research – Defining the “Ts” and T-Phases of Translational Health Research.
TM is extremely inter-disciplinary and a rapidly growing field in Biomedical Science. TM do not only brings specialists from various biomedical disciplines like biology, medicine, molecular biology, biochemistry, bio-statistics, bioinformatics; but also from chemistry (organic and analytical), physics and engineering. Yes, TM is as interdisciplinary as Biomedical Sciences or Pharmacy and Pharmaceutical Sciences.
The objective of TM is to combine the knowledge, resources, technology and applications of three pillars to facilitate the discovery of new diagnostic tools and therapeutic approaches using bench-to-bedside (B2B) approach through cross-functional collaborations between research scientists and clinicians, and using novel techniques and data analysis.
The basic research involves investigating fundamental science of human biology and pathobiology. People involved in basic science usually conduct research in the lab (bench work), which lead to identification of disease causing factors, drug targets (proteins or genes) and regulatory pathways (at genetic, molecular or cellular levels).
This part acts as a bridge between the basic science and clinical medicine. During this stage, scientists take forward the findings from the basic science (laboratory findings) to further understand the aetiology of the disease, and also work upon finding treatment. Whereas basic science is (or at least should be) non-targeted; pre-clinical research is always targeted towards a particular disease. Scientists test hypothesis using cells, tissues, animal models. Use of various computer-aided simulations is also very common in order to facilitate the development and preliminary testing of drugs and diagnostic tools (or devices).
Clinical research usually involves clinical trials of drugs in humans (patients and healthy volunteers) in academic medical centers and hospitals. The main objective is to test the safety and efficacy of the drugs (or diagnostic approaches); and to find out a correlation between a particular biomarker (disease marker) and patient phenotype (specific group of patients). One of the critical aim of clinical research is to obtain regulatory approval for a new therapeutic or diagnostic intervention.
The next stage is the clinical implementations that primarily involve new interventions becoming routine clinical care for the larger population, and conducting research to evaluate the findings from the clinical trials. This is one of the major stages that leads to new clinical questions for the basic science.
The final stage of translation involves evaluation of the health outcomes at the population level in order to determine the effectiveness of the new interventions for prevention, diagnosis and treatment of the disease. Findings may lead to working on improvements or development of new interventions.
Whereas the traditional science has been more about strengthening the existing hypotheses, TM is all about creating insights into clinically significant interactions among drugs, pathways, targets and diseases.
As you can see from the above image, the drug discovery process is a very long (time consuming) and expensive process. Approximately, it takes around 15 years and USD 800 Million to 3 Billion to launch a new drug molecule. The R&D process starts with around 10,000 compounds, out of which 5 compounds end up in the pre-clinical phase and finally the world gets 1 successful drug molecule.
Pharmaceutical companies, venture capitals and investors need to go through huge risk when it comes to spending on drug discovery. 75% of that money gets spent on the clinical trials and regulatory approvals. Even if a drug discovery project fails before the clinical trials (within the Drug R&D phase), investors might face a loss of around USD 100 – 250 Million. Whereas if the drug fails in any of the stages within the clinical phase, that will be a big ouch moment for the investors. Even the FDA evaluates drugs by their cost-effectiveness, so the end of the funnel needs to be large enough to justify the venture investment as well.
Before 1920, diabetes used to be an almost death case. Hence, insulin has been one of the most major triumphs in the history of medicine. The discovery and development of insulin therapy spanned over 150 years and that is the drawback of classical approach. However, it should be remembered that back in those days, the knowledge and technology were not that advanced.
Eli Lily launched Humulin, an intermediate acting the first product of recombinant-DNA technology; the advancements are still in process. Fluorolog (by Thermalin), an ultra-concentrated fast-acting insulin formulation entered clinical trials in 2014. There should be more success stories like Lipitor, one of the all-time blockbuster drugs that generated a revenue of USD 13 per year for almost a decade. For curious folks, here is What Really Drove Lipitor’s Success. It is tough to re-create a success story like that of Lipitor’s as Matthew Harper wrote Why There Will Never Be Another Drug Like Lipitor on Forbes, but there is certainly hope for creating cost-effective and fast discoveries through TM.
– To get the research from lab to benchside cheaper and faster; i.e.- accelerate the time process for bringing the intervention (drug. device or biomarker) from lab to clinic; and give the investors enough reasons to cheer about and keep investing at early stages.
– Create cross-functional collaborations among personnel working in different phases (basic science and clinic).
– Convergence of knowledge, technology and expertise from various disciplines and apply them to a common and targeted goal.
– To produce perfect solution for all patients, rather than just coming up with an okay solution for many patients. In a perfect world, hardly there is any drug that interacts with a single target that is linked to a particular disease.
Whether the investment and efforts produces a result or not depends largely on genomic studies (sequencing) that can identify the set of patients most likely to respond to a new drug molecule. It would be unwise to expect a single drug treat all kinds of cancer. For example, Dabrafenib (GSK2118436) and Trametinib (GSK1120212) – two drug candidates from GlaxoSmithKline (GSK), reached the clinical phase with the aim of treating patients with advanced or metastatic melanoma with BRAF V600 mutation. Similarly, Roche and some other companies are also trying a similar approach to treat patients with BRAF V600 mutation. For interested folks – Role of BRAF V600 Mutation in Melanoma.
The advantage of translational medicine has been proved in both early phase and late phase drug discovery. TM provides feedback to pre-clinical scientists for further studies on an ad-hoc basis. During the final pre-approval stage TM provides insights into the target populations that may have a selectively better outcome and thus creating doors for personalized medicine. Hence the quest of finding new biomarkers is getting a lot of importance in order to stratify patient populations properly and provide a quantitative evidence of the benefits from the interventions. Modern translational medical researchers are even hoping to take the field to single patient level through stem cell technology in the coming future.
I have had quite a considerable exposure to different phases of translational medicine in four different labs across three different countries.
During my MSc thesis at the Aston University, I worked on studying the mechanisms for the physiological actions of the CGRP protein. The CGRP protein is known to modulate various physiological functions and plays a major role in migraine and cardiovascular disorders. The CGRP protein exerts its actions through CGRP-Receptor (also known as CALCRL) and RAMP1 protein. My project was specifically on investigating the role of RAMP1 in receptor-protein binding and interactions between CGRP-receptor and Adrenomedullin. I was not working to find something new, but to re-confirm the hypothesis (reproducing previous findings are also considered as important as finding new results). The implications of receptor studies are always to lead to findings for new drug molecules. Without proper knowledge about how a receptor binds other molecules (or proteins), it is not possible to synthesize chemical compounds to target a specific receptor. I would term this study as basic science and the findings had the potential to lead to discovery of new medicines (or better medicines) to treat migraine (and many other disorders).
After finishing my Masters, I joined the Cardiovascular Division (Radcliffe Department of Medicine) at the Welcome Trust Centre for Human Genetics, University of Oxford. I worked on the protein called Creatine Transporter (CrT); and to be specific, myocardial CrT. For general audience – CrT is the protein through which creatine (supplies energy to cells in the human body) enters the cells. In case of low levels of creatine (Phospho-Creatine in correct scientific term) the heart cells starve of energy and that leads to myocardial infarction (heart failure or heart attack). My primary objective was to optimize a screening protocol and find chemical compounds (in collaboration with the Chemistry Department) to regulate the levels of myocardial creatine (in vitro), and any significant increase in the levels of myocardial creatine has got the potential to be beneficial in case of heart failure. This time I had a specific objective (targeted goal) while working on basic science in the lab; hence this was clearly a case of Pre-Clinical Research. During the project I did find few compounds that increase the cellular uptake of creatine and also identified few proteins that regulate the action of CrT. One of most important findings was the role of TXNIP for regulating CrT, and we also published a paper on that – A role for thioredoxin-interacting protein (Txnip) in cellular creatine homeostasis. In addition to that, the screening method that we optimized in order to identify new drugs also got patented.
After a successful stint at Oxford, I moved to the Netherlands in search of new challenge and excitement. I was based at the University Medical Center Utrecht, and my project was discovery and novel biomarkers for prediction of cardiovascular events (heart attack, stroke, death etc.). I had the opportunity to work with human tissues (atherosclerotic plaque samples) and human samples (blood, plasma, and serum). I used to measure protein levels in healthy volunteers and patients and was trying to figure out the proteins that were elevated (or decreased) in patients in comparison to healthy people. After identifying the differential proteins, we were also used to study the basic biology and mechanisms of their actions, particularly of Osteopontin. This was something pre-clinical study and taking the findings from clinical studies back to lab bench.
The fascination for proteins and translational medicine took me to Down Under, where I took up another research position at the St. Vincent’s Centre for Applied Medical Research, affiliated to the University of New South Wales (UNSW) in Sydney. At UNSW, I was working on GDF-15 (also known as MIC-1), which is a biomarker for various types of cancer. It was also pre-clinical research with tremendous potential for translational medicine. For the first time, I gained hands-on experience on animal models (in vivo studies).
I had my Bachelor studies in Pharmacy (Pharmaceutical Sciences) and then moved to the United Kingdom to do my Masters in Pharmacology. It was a great learning curve as I gained exposure to different stages of Translational Medicine across various research areas. There is no hard and fast path for pursuing a career in translational research. Of course a Biology background is helpful, but you can also end up in TM with engineering background. Read the blog of Mechanical Engineering Graduate Ending Up in Translational Research. Most of the research these days is translational in nature. If you end up doing a PhD following basic or applied biological (or biomedical) science, you will have excellent scopes to conduct translational research. Recommended reading – Tips for Getting a PhD in Biomedical Sciences. Besides, there are few specialized Masters Programs that can give a perfect boost for a career in the translational medicine.
Those who are interested in the field of Translational Medicine, should possess the “breadth”, as quoted by Robert Hertzberg of GSK. According to Hertzberg, a Physician or Medical Doctor should know about basic science and should have spent time at the bench in order to have a good and meaningful career in TM. Hertzberg further recommended moving around different parts of an organization instead of staying in a single niche. An ideal training would be to join an academic medical center (or clinical center) where you gets exposure to both basic scientific research and dealing with patients or clinical samples. A rounded experience backed by solid knowledge of basic and clinical science will be the key to career progression.
India has already been proved to be strategic location for conducting clinical trials by several multinational pharmaceutical companies. Besides, India is also rapidly getting in to a position for contributing towards drug discovery by adopting the translational framework. India has got a large pool both in terms of patients, and qualified and talented personnel. Other significant advantages are lower costs and English being the official language in the medical profession. Then there is the support from the Indian Government as well. Prime Minister Narendra Modi had declared USD 28 Billion spending on Universal Healthcare Scheme, which will provide free check-ups for everyone. This will provide an enormous clinical data. India has already got state-of-the-art data processing infrastructure for bioinformatics and biostatistics; and rapidly adopting the translational framework.
The set up of Translational Health Science and Technology Institute (THSTI), backed by the Ministry of Science and Technology (Govt. of India), in Gurgaon (2009) has been a critical step for revolutionizing translational research in India. THSTI has got a partnership with Harvard-MIT HST for infrastructure development and training. Courtesy to THSTI, the Drug Controller General of India (DCGI), Scientific Review Committees (SRC), the Indian Government, a healthy clinical trial infrastructure is getting set up all round the country. India is rapidly adopting a translational framework and all poised to narrow the gap between basic scientific research and clinical research as per the Critical Path Initiative of FDA. Hence, the prospects are quite bright for translational medicine in India.
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