Biomarkers - main drivers of innovation

Biomarkers are rapidly becoming the main drivers of innovation in the 21st century. Because they improve the potential to tailor treatment to the specific needs of individual patients, they are a critical prerequisite to personalized medicine.

BIOCRATES Life Sciences AG identifies and quantifies endogenous metabolites in body fluid or tissue samples and develops them into powerful biomarkers. By focusing on metabolites, Biocrates  looks at the functional endpoints of diseases and drug action - a  technology called metabolomics.

Cutting-edge biomarker research stands to benefit everyone.

• Research organizations will be able to enrich their diagnostics and drug development programs and save costs by better targeting their projects.
• Physicians will be able to predict disease risk more reliably, establish diagnoses earlier, and tailor treatments more individually.
• Patients will benefit from treatments that are more efficacious and have fewer side effects.
• Biocrates' research and development focus rests on two pillars:
• One is the identification and validation of powerful biomarker panels that help identify disease risk, diagnose diseases, assess disease severity, and guide treatment. Biocrates has developed a comprehensive biomarker pipeline, covering indications from chronic disorders, such as type II diabetes, to acute events, such as stroke.
• The other is to support other research organizations in developing biomarker panels that help assess how a new drug works in the body and identify patients most likely to respond to a treatment or least likely to suffer side effects. Such biomarkers, which are becoming part-and-parcel of the design of targeted therapies, are referred to as companion diagnostics.

This innovative, fully integrated technology platform for metabolomics is based on mass spectrometry, enabling the systematic quantification of a wide range of biologically relevant molecule classes in a wide range of samples, from blood and serum to cells or tissues.

This relatively new field of systems biology attempts to reveal the complex interactions between biological systems at a molecular level. Until recently, systems biology has relied on genomics, transcriptomics, and proteomics. Trailblazing as these areas have been, they do not tell the whole story of what is happening in a cell. Recent advances in mass spectrometry have now added yet another powerful tool to the armamentarium of systems biology, i.e., metabolomics, or the study of the metabolome - the collection of all metabolites in a biological system.

By being able to simultaneously assess thousands of metabolites, modern mass-spectrometric techniques produce high-resolution biochemical snapshots depicting the functional endpoints of genetic predisposition and the sum of all environmental influences, including nutrition, exercise, and medication. This snapshot is a reflection of the physiology - or pathophysiology - of a cell or an entire organism.

There are two approaches to metabolomics, i.e., targeted metabolomics and metabolic profiling. While both approaches are complementary, targeted metabolomics, i.e., the identification and quantification of defined sets of structurally known and biochemically annotated metabolites, takes advantage of our detailed understanding of most biochemical pathways. In contrast to protein-protein-interactions or regulatory relationships at the transcript level, the vast majority of enzymatic reactions is well characterized, i.e., products and substrates of a reaction are known, as are its cofactors and often even its kinetics, equilibria, and energetics.

One major advantage of targeted metabolomics is that it generally provides quantitative information. These quantitative data - the molar concentrations of the metabolites involved in a pathway - facilitate the immediate understanding of deviations from homeostasis. Interpretation of targeted metabolomics data is straightforward, regardless of the cohort investigated, i.e., healthy or diseased, treated or untreated, etc. Also, it reliably identifies enzymes or pathways responsible for any observed alterations. Another advantage of targeted metabolomics is that it is well suited for high-throughput and routine applications.

BIOCRATES has developed an innovative, fully integrated technology platform for targeted metabolomics that enables systematic quantification of a wide range of biologically relevant molecule classes in cells, tissues, or clinically relevant fluids. The technology comprises an automated sample preparation workflow integrated with sensitive mass-spectrometric methods and a tailor-made software solution. Many hundreds of metabolites can be identified and quantified using this novel platform.

The proof-of-concept for targeted metabolomics was first established in routine clinical diagnostics, i.e., in the screening of newborns for inborn errors of metabolism. Since the late 1990ies, the diagnosis of inherited diseases has been revolutionized using mass-spectrometric assays for quantifying sets of amino acids and acylcarnitines-a development co-pioneered by one of Biocrates' founders. This project has taught the company some crucial lessons:

First, quantification of endogenous metabolites using multiple reaction monitoring (MRM) and stable isotope dilution (SID) on tandem mass spectrometers is able to fulfil even the most stringent quality criteria regarding precision and accuracy without suffering from cross-reactivities and other shortcomings of immunoassays, and is, therefore, an ideal technology platform for clinical chemistry. Second, the theoretical assumption that multiparametric biomarkers would, by internal normalization, be able to reduce biological noise in the data, thereby improving sensitivity and, particularly, specificity of the diagnoses, has turned out true for many disorders. Third, the improved diagnostic performance was achieved without raising costs. On the contrary, neonatal screening is now reimbursed by health insurance providers in many Western countries and has lead to substantial savings for the public health systems. These medical and commercial benefits have made neonatal screening an impressive success story and led to its introduction in most industrialized countries within less than a decade.

With the diagnostics industry constantly searching for new ways to detect diseases as early on as possible, metabolomics is here to stay. Because metabolomics looks at the functional endpoints of biological processes, metabolomics-based markers will be more predictive and descriptive than just measuring risks and predispositions, which is what genomic and proteomic markers do. Metabolomics will help trigger a paradigm shift from damage-oriented to function-oriented diagnostics. Ultimately, these shifts will enable diseases to be detected before they cause irreversible damage to the body.

In pharmaceutical development, metabolomics has likewise carved out a secure place for itself. Thus, a close look at the metabolome can help pinpoint new drug targets, prioritize lead compounds, and assess the toxicity of drugs.

In clinical medicine, metabolic biomarkers will increasingly be used to determine patient populations or subgroups who, based on their metabolome, will actually benefit from a given treatment. Once responder status has been established, these biomarkers - or companion diagnostics - will help monitor drug safety and efficacy, thereby guiding therapy decisions and enabling the clinician to personalize treatments to the specific requirements of each patient.

BIOCRATES has, over the years, established itself as an expert in metabolomics and biomarker discovery and will continue to put its extensive know-how to use to develop diagnostics that act as companions accompanying specific drug treatments and guiding physicians in making personalized treatment decisions.