Switching the Bait

Turning a standard technique into an unbiased screen for diagnostic biomarkers

Feb 1, 2012
Edyta Zielinska

Screening for antibody biomarkers of disease to facilitate diagnosis has been fraught with failure, despite its logical approach: stick proteins onto a microscope slide and then pour over a patient's serum, full of disease-specific antibodies, and see what sticks. Compare the results to the serum of a healthy person, and you've got an antibody-protein pair that should signal disease. But of the proteins IDed employing that method, "none of them are even close" to clinical diagnosis, says Thomas Kodadek, at the Scripps Research Institute in Jupiter, Florida. Kodadek and his colleagues figured that the antibodies in the serum of an ill individual wouldn't be likely to bind to normal biological proteins. The immune system recognizes the foreign proteins of an invading pathogen or the markers of a dying cell precisely because they are different from the body's normal proteins. A cell involved in a disease like cancer or Alzheimer's is more likely to produce altered proteins, either because of genetic mutations or because the disease process changes the cytoplasmic environment, causing unexpected posttranslational changes.

But trying to guess what those chemical alterations might be is difficult. "We have absolutely no freakin' idea what those events are," says Kodadek. So instead of coating the slide with known proteins, Kodadek coated a glass slide with a fairly random assortment of unrelated synthetic small molecules that bind serum antibodies simply because of their chemical shapes, allowing for a broad and unbiased search. "The difference is what you're fishing with," he says.

The method "represents a major advance in the field," says Bill Robinson of the Stanford University School of Medicine. "It could enable the identification of the antigen targets for multiple autoimmune and other diseases."(Cell, 144:132-42, 2011)


PROTEIN ARRAY Unaltered protein Glass slide with proteins $1,500 (commercially made slides) Several thousand per slide
KODADEK'S METHOD Synthetic molecule Glass slide with small molecules $10 (lab-made slides) Potentially millions (if beads are used in place of slides)