What is translational science? This is a question I get asked frequently, by both academic and industrial scientists trying to understand the ‘new kid on the block’ in terms of placement within a bioscience discipline. Rather than go through the well worked phrases of science that goes ‘from bench to bedside’ or from ‘mouse to man’, a more accurate definition might be ‘the application of biomedical research (pre-clinical and clinical), conducted to support drug development, which aids in the identification of the appropriate patient for treatment (patient selection), the correct dose and schedule to be tested in the clinic (dosing regimen) and the best disease in which to test a potential agent (disease segment)’. A challenge to say, let alone do, but it is fast becoming one of the most exciting research areas for pharmacologists to work in, as they get to see the translation of their hypotheses into the clinic for testing.

In simple terms, translational scientists, both in industry and academia are aiming to answer some simple questions once a drug candidate has emerged from a screening cascade. These include:


• What disease might this agent work in? By testing in a number of pre-clinical models of human disease and working out whether this is predictive of disease in man some direction can be provided pre-clinically.

• What dosing schedule can we test in the clinic for maximum therapeutic benefit with minimum toxicity, based upon the scientific profile of the molecule and data from pre-clinical models?

• Can we use pharmacodynamic ‘biomarker(s)’ (measures of biological effect in man) to determine whether the compound blocks or stimulates the target receptor or enzyme in man as it does in animals (commonly known as proof of mechanism)? What effect does modulating the target have on the cellular phenotype that we might be trying to modulate (known as proof of principle, or proof of biology)? Does induction of this phenotypic change result in therapeutic benefit to the patient, and at what dose does this occur in the patients (proof of concept)?

• Can we identify patients from within a disease population who might benefit from the agent, either by a gene mutational change or an over/under-expression of the protein target receptor or enzyme as examples?

• If an agent is being developed as second or third in the market place (usually termed a ‘best in class’ agent), what differentiating pharmacology might this compound require in order to encourage regulatory agencies, physicians, and patients to test it?

Technical platforms that are used in these investigations include preclinical in vitro, in vivo, and clinical pharmacology, genetics, biomics (genomics, proteomics, and metabonomics), pharmacokinetic and pharmacodynamic modelling, histopathology, imaging, and serum marker measurements. The key element in all these platforms is that they have to be transferable to the clinic and usable in man. If a terminal bleed or organ removal is required to measure a biomarker pre-clinically, you can be guaranteed that this won’t have application in the clinical setting!




Given the ever-increasing cost of drug development, and the fact that for each new chemical entity registered as a drug there are nine others that fall by the wayside, it is important to identify the effective ones early in the drug development process. Use of biomarkers, combined with early clinical efficacy read-outs can define whether an agent has achieved the proof of mechanism, principle, or concept hurdles required to progress further in development. It allows drug developers to make ‘go/no go decisions’ on compounds.

An AstraZeneca example of biomarker use is demonstrated in figure 2 where the agent being tested inhibits a kinase involved in cellular division. The proof of mechanism biomarker is the phosphorylation of a protein that the kinase induces. Blockade of the kinase with the agent inhibits phosphorylation; shown pre-clinically in a mouse tumour xenograft study where the dark staining cells are reduced in number and intensity, compared to a pre-dosed animal. This blockade was also demonstrated in human volunteers where the protein phosphorylation was inhibited in normal buccal cavity tissue. Subsequently, this activity was also demonstrated in skin and tumour tissue (not shown) in patients with cancer.

There are three key elements to being a good translational scientist. Firstly, and not surprisingly, a good working knowledge of biological science is essential, together with the ability to apply the technical platforms from the lab into the clinic in a given disease. Secondly, project management skills are key when working to deliver appropriate biomarkers. It can take up to two years to validate a biomarker ready for clinical trial use, which may mean that the translational scientist has to work to tight timelines to deliver a reproducible biomarker within the time from drug candidate identification through to application in the clinic.

Finally, excellent inter-personal skills are required for successful translation through to the clinic. Usually the translational scientist works with experts in the technical area to develop the biomarker, and with the physicians and research nurses who will be responsible for taking the compound into man. In order for all the elements of the translational science to be delivered, teamwork is essential. The team needs to define how to take the blood sample/images/tissue and measure the biomarker in a robust and reliable way. They then need to gain permission from regulatory agencies and ethical boards to dose the patients in a safe manner and take the samples in the appropriate way. Finally, together as a team, they need to interpret the data from the clinical trial which, unlike pre-clinical experiments, cannot be repeated if samples are lost.

To say that translational science is a challenging arena to work in is probably a typical British under-statement. To say that it is ‘sexy’, exciting and a little bit more than ‘just pre-clinical and clinical pharmacology’ is probably true.




Donna Johnstone
Director of Discovery Medcine in Cancer Research
Astrazeneca, Aldeley Park