A biomarker is a biological variable that reflects a physiological change, e.g. as a result of disease, drug treatment or some other external influence. Through them, the body signals a biological response to a change. By identifying and studying biomarkers it is possible to demonstrate the desired effects of a drug without needing to study a compound’s impact on the symptoms of a disease.

Important tool

When a drug encounters a target substance this evokes a response, which in turn affects the biomarker, the concentration of which increases or decreases, for example. Samples are then taken, e.g. of blood or urine, and the results show whether the drug has had the desired effect. Examples of biomarkers are proteins, peptides, nucleic acids, carbohydrates and lipids.

"With the aid of biomarkers, we can achieve greater confidence in our candidate drugs and more reliably predict how they will function in humans in early clinical trials, prior to time-consuming and costly clinical experiments. Our goal is to find markers which will provide us with information on how the substance will function in humans," says Dr György Marko-Varga, Principal Scientist at AstraZeneca and chair of our global proteomics network.

Emphasis on proteins and peptides

"Within AstraZeneca there is currently a major emphasis on the study of proteins and peptides. We have developed a technology platform that can identify these biomarker candidates specifically and with great sensitivity" explains Dr Marko-Varga.

Nearly all diseases are in some way connected with proteins – which are crucial to cells and organs. Production of proteins may be insufficient or unsuitable or they may not be functioning normally. Most modern small molecule drugs target proteins and therefore we can measure levels of specific marker proteins to gauge the compound’s potential effectiveness disease status in drug trials.

"If you include all variants there are doubtless several million distinct protein structures in humans," says Dr Marko-Varga, pointing out that a number of forms only exist for specific, often extremely short periods of time. Others only exist in minute quantities. Mapping and analysing protein structures in defined biological systems, e.g. blood, liver, plasma, urine or sputum, form the core of proteomics. Proteomics can be used to identify key markers that may be targets for drugs.

Equally important, mapping and analysing peptide structures in defined biological systems forms the core of what is known as peptidomics. Dr Marko-Varga explains:"The difference in peptide level we see between patient groups and healthy individuals forms the basis of our biomarker candidates.”AstraZeneca has specialised in developing technology that can analyse thousands of peptides from biological fluids and tissues.

Identifying diseases' 'fingerprints' – biomarkers

Proteomics and peptidomics research are very useful throughout the entire research process. The aim is to be able to correlate specific protein and peptide expression profiles or 'fingerprints' to defined diseases or reactions to medicines.

"If we succeed in that we can increase our understanding of diseases and improve the possibilities of pharmacological intervention with good results," says Dr Marko-Varga.

Improving legibility of the biology is a technological challenge. The boundaries are set by technological developments, but according to Dr Marko-Varga the biological complexity also sets boundaries*. In the field of genetic research it is possible to duplicate large quantities of genetic material, but there is no equivalent technology in the field of proteins or peptides. "Using more biological material is the only solution, but gaining access to it is not always that easy," he says, adding that we also need access to a well segmented and well-characterised patient population to facilitate correct correlation of the biomarker expression to the stage of the disease.

New guidelines pending

The global organisation Human Proteome Organisation (HUPO) is studying expression of proteins in various programmes. One of the most important programmes is the Proteome Standards Initiative, which will provide a standard for the criteria to be met to facilitate establishment of a protein's identity. "This will be instructive for us at AstraZeneca," says Dr Marko-Varga. It is very likely that the global databases AstraZeneca generates in various areas of disease will in future have this standard as their basis, thus making our data directly compatible with all other public academic databases.

* The use of biological material (blood, cells etc) must satisfy the requirements of the new Biobank Act. A biobank is a collection of samples that are looked after and saved for over two months and that can be traced to a specific person.

Published 13 April 2005