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Strategic screening enables effective biomarker discovery

During my eight years at the Max Planck Institute for Molecular Genetics in Berlin, I led a protein technologies group. We developed a protein expression library, and then high-content protein arrays. In total, we made arrays with 10,000 different human proteins.

Twenty years ago, we were able to take a small amount of blood, plasma or serum, i.e. a liquid biopsy, and incubate that on the array. This would only take an hour or so, and then we profiled which proteins the serum antibodies were binding to on the array. We did this with thousands of human proteins, and for hundreds of patients. By comparing patients with different diseases, we are able to profile different antibody responses for cancers and autoimmune diseases, thus identifying which proteins were biomarkers for various diseases.

On the back of this Protagen was founded, which has been working these past twenty years with the pharmaceutical and diagnostic industry to develop diagnostics in autoimmune disease and cancer.

A long term protein array

We realised by thinking about things in a 20-30 year time frame we could actually design the next 20-30, or even 40 years of research to array the proteins with internal controls. This has allowed us to compare experiments from over a 20-30 year timeframe.

In 1998 we screened 200 patients with an autoimmune disease against the same 10,000 proteins. Then 10 years later we screened another set with different autoimmune diseases, but always screening the different cohorts against the same array, where the proteins have been arrayed in the same order. Protagen has screened 20,000 clinical samples in different diseases, and I have screened thousands and thousands in my group.

Therefore we can actually compare which proteins appear in various diseases over the last 20 years. Every time we do a new experiment we can screen the results in that disease, but also look back over time and ask, “does the protein which came out in this particular disease appear in any of the other diseases we’ve done?” 

We did enough aliquots that we can still use the original subject’s blood and then compare the results we got in those experiments – it’s a highly reproducible process. Then we can do the analysis with different cohort completions over time and see which biomarker will come up in one disease but not in any other.

In all the arrays, we have had a lot of internal controls and standard operating procedures. So we can look and see that we have standard reproducibility and standard blood samples that we used in every experiment from 20 years ago.

By thinking about the experimental design and comparing it with other experiments, we can end up with a useful biomarker and diagnostic tools. 

Strategic biomarker research

So many experiments are badly designed and thus wasteful. It would be much better for countries to take a lead on strategically designing research into one or two diseases. Non-invasive liquid biopsies can be used with extensive protein libraries and compared with data across different diseases and through time. This deliberate, proactive and coordinated approach is what will enable genuine identification and validation of biomarkers.

These project might take up to 16 years and involve multiple PhDs, but it would enable the possibility to do adequate biomarker screening and develop precision diagnostic tools.

 

Dolores Cahill is Professor of Translational Science at University College Dublin, Ireland.

 

At the Liquid Biopsies Congress: Europe, talks will review techniques for single use molecules and selective enrichmentClick here to download the agenda.

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