Professor, Biochemistry/Microbiology Department
Senior Scientific Advisor to the Plasma Proteome Institute, Washington, DC
Phone: (250) 721-7080
Research area: immunochemistry of parasitic diseases, plasma proteomics, immunodiagnosis
Antibodies are a powerful tool for diagnosis, used in everything from HIV tests to home pregnancy tests. However, there are several areas where antibody-based diagnosis has been disappointing and has, frankly, stalled – like detecting early stages of cancer through biomarkers.
Biomarkers are proteins produced by a disease such as cancer that could alert clinicians that a tumour is forming. There are over 4,000 potential cancer biomarkers published in journals, yet only a few are used in the market today, for example to diagnose breast cancer, and for prostate cancer.
Dr. Terry Pearson wants to break through the stalled science of classic antibody work to unlock the potential of those biomarkers, and he thinks emerging mass spectrometry techniques are the trick to help him do this. Working with about 50 researchers in a collaboration that joins UVic with the Broad Institute of MIT and Harvard; the Plasma Proteome Institute in Washington DC; and the Fred Hutchinson Cancer Research Center in Seattle, Pearson is developing a new technique that he thinks will fish out and quantitate antigens in blood plasma that indicate cancer.
Mass spectrometry has advanced tremendously over the last decade, moving from a technique that once only identified small molecules, to a method that can identify fragments of proteins, called peptides, from blood plasma. Lucky for Pearson, UVic is home to the University of Victoria - Genome British Columbia Proteomics Centre, renowned for its mass spectrometry peptide work.
There are several reasons current protein measurement techniques are inadequate for pursuing cancer biomarkers, Pearson explains. For one, despite advances in protein chemistry, it is still laborious (I know, but it’s ugly) and expensive to isolate and purify proteins from a complex mixture, such as blood plasma. This makes developing monoclonal antibodies against biomarkers in blood expensive. In fact, Pearson says that it costs from two to four million dollars to develop antibodies sensitive and specific enough to detect and measure a potential biomarker. “And that is before you even know it is a good biomarker, useful for developing a clinical test” he adds.
To be a good biomarker, it would have to be found in all patients with the same cancer, and be found early enough in the disease process to make a prompt diagnosis. Given the variety and individuality of cancers, the odds of finding such a biomarker are not good. Chances would improve if the process of testing antibody-antigen pairs become high-throughput. Ideally, a researcher would find a way to validate hundreds of biomarker antigens at once. Pearson thinks such an assay is possible with mass spectrometry. So far Pearson and his collaborators have managed to screen for 20 biomarkers at once.
It works like this: Pearson and his collaborators are using a set of criteria to design peptide epitopes for 225 potential breast cancer biomarker proteins, based on their protein sequences. They will then synthesize these epitopes and use them to derive monoclonal antibodies. They will use the resulting monoclonal antibodies as ligands or probes to enrich the peptides from blood plasma from cancer patients. Finally, they will use mass spectrometry to identify the peptide, ensuring it is the one they designed and are fishing for. If the antibody works well enough, they can use this process to screen thousands of cancer patients to validate the biomarker.
To scale up the process, Pearson thinks that soon they will be able to use 100 different antibodies at once to enrich 100 potential biomarkers, which can all be identified within seconds once injected into the mass spectrometer.
Beyond cancer, the same process would be used to identify and qualify potential biomarkers for other diseases such as those caused by bacteria, viruses and parasites. One area that Pearson is already working on is African Sleeping Sickness – his life long passion. More...
To add another element to their technique, Pearson and his collaborators are incorporating labelled standards to quantify biomarkers. This is especially useful in cancer diagnostics, where often an elevated amount of a biomarker, rather than just its presence, indicates disease.
It is especially fitting that Pearson is taking antibody diagnostics to the next level, since he was there at the inception of monoclonal antibody research. Early in his career as a staff scientist at the Laboratory of Molecular Biology in Cambridge, England, Pearson collaborated with Georges Kohler and Cesar Milstein during their development of monoclonal antibody technology. His lab at UVic has continued to be at the forefront of developing antibody-based techniques ever since.