Following extensive research among the pharmaceutical industry, there is a growing trend in what is known as "Translational Medicine". Translate the knowledge of basic sciences into the clinical research and treatments are the domain of translational medicine. The science in the age of information has grown into what is called as information jungle. Lots of discovery and new knowledge is available with a click of mouse. How do we use it effectively is a challenge faced by many scientists and healthcare providers worldwide. The focused approach to determine what is limiting in the current clinical practice has come to the knowledge recently by clinical research. The drugs are to be valued on their clinical efficacy and safety has made it mandatory to its licensing has ushered into a new discipline of medicine what is called as translational medicine.
Translational medicine can be better appreciated if one asks these questions in a clinical setting.
When a new drug enters into a clinical trial it has to pass the litmus test of following queries:
A) Whether every one treated will respond similarly? Or they're variations of drug responses due to pharmacogenetics.
B) What are optimal dosing levels? A proof for its adequacy.
C) How to get convinced that drug is really making differences in Pathophysilogy due to its intervention? How do we go about proof of concept?
D) What patients are likely to have side/adverse effects more severely, can we classify the patient population on this basis?
It would be wishful criteria but appearing more theoretical and difficult to bring it to practice. However, as we see the translational medicine has evolved to address such difficult queries and is practiced in many clinical researches. The specific biomarkers are carefully identified to answer the specific question, which translates these difficult questions into definite answers making clinical research a quantitative science.
For example, to answer what subjects are most likely to respond specific biomarkers like Her2/neu in breast cancer, EPGR mutations in non-small cell lung cancer, and DWI/PWI mismatch in ishemic stroke has been successfully used in drug evaluations. Regarding optimising the dosing regime receptor occupancy studies with the help of PET imaging of ligand displacement studies have been successfully applied. The biomarkers like reduction of amyloid burden by PET in Alzheimer disease, Change in cytokine profile in inflammatory disease and change in glucose uptake by tumours are successfully used asses earlier alterations of Pathophysilogy of diseases. The genetic profile of genes like G6PD, Cytochrome 450 variants or genes pertaining to hemorrhagic or cerebral stroke would give an idea of pharmacogenetics basis of variation of drug effects. Early identification would resolve the issue of variation of drug responses.
Educational programmes in translational medicine
Many prestigious universities and healthcare schools are offering educational programmes in translational medicine and there are dedicated journals, which publish research articles routinely. There are international events happening repeatedly all over the world to discuss the advances in translational medicine. These recent upsurges in interest have bearing in change in approach of patient centric therapeutics from industrial dominated mass drug discovery. The science is revealing several secrets like variability to drug response and its importance in drug activity is very important which can add value to patients well being. Emergence of pharmacogenetics as a major area of practice has raised hopes of individualisation of drug therapy.
Another approach in translational medicine is to pool data during clinical trials itself, the out come of treatments from the actual patients in the course of trials. After all how the patient is finding the treatment helping him to cope with the disease is ultimate test that is going to matter when the drug is actually enters into a market. The patient views and feeling regarding outcome of treatment could be a paramount significance in the performance of the drug in a market. Many companies are conducting the surveys and collecting data on patient's view of treatment. This will give the development team an opportunity to understand pit falls of molecules and what type of corrective measures need to be taken to over come. The value of data collected in the course of clinical research could be increased if the correlations of cognitive behaviours with EEG results and MRI scanning are looked in an integrated analysis. This approach is of very grate value in the drug development of CNS acting drugs.
Development areas
Some of the interesting areas of development in translational medicine involve in the evaluation of anxiolytic using experience of human subjects under clinical research. Correlating the heart rate variability and skin conductance studies as measure of anxiolytic effect. Urotensin-II (U II) is a cyclic peptide that acts through a specific G-protein coupled receptor, UT receptor. Urotensin-II and UT receptors have been described in pancreas and kidney, but their function is not well understood. The effects of chronic treatment of diabetic rats with the orally active selective U-II receptor antagonist palosuran. Streptozotocin treatment causes pancreatic -cell destruction and leads to the development of hyperglycemia, dyslipidemia, and renal dysfunction.
Long-term treatment of streptozotocin-induced diabetic rats with palosuran improved survival, increased insulin and slowed the increase in glycemia, glycosylated hemoglobin and serum lipids. Furthermore, palosuran increased renal blood flow and delayed the development of proteinuria and renal damage. The U-II system is unique in that it plays a role both in insulin secretion and in the renal complications of diabetes. Urotensin receptor antagonism might be a new therapeutic approach for the treatment of diabetes. Application of Urotensin II antagonism as a biomarker for establishing the efficacy of antidiabetic drug is on the agenda. Many drug are known to prolong QT interval. This observation may be an early indicator for forecasting the cardiac safety of the drugs under investigation.
Resources for translational medicine
The potential resources for translational medicine are drug interactions, which can be easily observed in vitro studies, drug metabolism studies during their preclinical development. The advances in diagnostics and drug discovery were purely driven from industrial point of view has a paradigm shift in recent years. The problems and limitations of clinical evaluation are driving force for development of new drug. The translational medicine best described as bench to bedside research to highlight the reorientation the research practices.
How are these defined, what uses are there and what are the benefits? Translational medicine is a branch of medical research that attempts to more directly connect basic research to patient care. The medical information and literature are so much diverse that intrepetation in terms of commercial aspect becomes often confusing and usually ends up with wonderful marketing stratergies with end results often dangerous outcomes. It is often necessary to identify risks at the early stage of drug development. Translational medicine is growing in importance in the healthcare industry, and is a term whose precise definition is in flux. In particular, in drug discovery and development, translational medicine typically refers to the "translation" of basic research into real therapies for real patients. The emphasis is on the linkage between the lab and the patient's bedside, without a real disconnect. This is often called the "bench to bedside" definition.
Translational medicine can also have a much broader definition, referring to the development and application of new technologies in a patient driven environment - where the emphasis is on early patient testing and evaluation. In modern healthcare, we are seeing a move to a more open, patient driven research process, and the embrace of a more research driven clinical practice of medicine.
Many pharmaceutical companies are building translational medicine groups to facilate the interaction between basic research clinical medicine, particularly in clinical trials. Traditionally, basic research has been separated from the clinical practice of medicine by a series of hurdles or fences. New drugs were developed independently of the clinic, and often "thrown over the fence" for safety testing and clinical trials. The move toward translational medicine is focused on removing these fences, and stimulating "bench to bedside" research.
The upsurge or a awareness of a serious adverse effect of molecule in advanced stage of development would be disastourous for development promoter. Cardiovascular side effects of selective COX II inhibitors is an eye opening for regulators and developers as well. The molecules and its interaction with biosystems is very complex to define and understand. However, what kind of outcome it is causing if carefully falllowed in all its stages of development, it could be like a stich in time saves nine. So in order to make a critical evaluation of the clinical outcomes there needs to be all together new concepts and specific to disease conditions. For example in order to evaluate anti cancer agent ,the drug saftey is to be established and its efficacy in controlling growth of cancer in the course of treatement need to be established. For this there should be special diagnostics which not only give information on the cancer prognosis but patient also on condition. The preferential diagnostics should be non invasive and should not cuase any discomfort for the patient in the course of dignosis. The application of science to develop a technology meeeting the just descibed criteria is Translational medicine. The clinical trials and research has become more objective intensive on application of translational medicne.
The US FDA, the champion in drug regulation, recently described concept of critical path initiative which coins the link between translational medicine to clinical research. It states that "Critical path research is directed toward improving the medical product development process itself by establishing new evaluation tools. Together with academia, patient groups, industry and other governmental agencies, we need to embark on an aggressive, collaborative research effort to create a new generation of performance standards and predictive tools that will provide better answers about the safety and effectiveness of investigational products, faster and with more certainty." It also viewed that by practice of translational medicine it is possible to identify the promising molecules in the early stages of development. It also regretted the development scientists are showing less interest in using the data outcomes in decision making of drug development.
The emphasis of translational medicines is to perfect the diagnostics which could identify the future problems that is likely to surface in the course of drug development and its application. The translational medicine should be able to guide the path of drug development. In the era of molecular biology, the role of molecular diagnostics cannot be ignored. It is possible to study the effect of drug on gene expression in cell lines and also possible to any adverse effect due to genotoxicity in the early stages of development itself. Hence the regulatory agencies are of the hope that translational medicine would be a boon to establish a drug profile of risk/benefit in early stages of development it self. Hence, it is not surprising the US FDA declaring a protocol of critical path research for a clinical development of drugs. The advent of specific biomarkers has in fact made it easy to correlate the data from animal studies more realistic prediction in human treatments.
Using new genomic and proteomic tools, researchers are now engaged in an unprecedented large-scale hunt for new biomarkers. Because modern molecular biology and cell biology are so closely linked to cancer research, that family of diseases has received the lion's share of attention, but a few scientists are now developing molecular biomarkers for other prevalent conditions, like heart disease and brain injury. While borrowing some techniques from cancer research, these investigators are also developing some of their own approaches, and discovering some of their own obstacles.
(The author is with Pharmacy Group, Birla Institute of Technology and Science, Pilani, 333031, India.anantha@bits-pilani.ac.in)