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Crimson Chips: High in Protein

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Combining biology with chemistry, Gavin MacBeath of the Center for Genomics Research at Harvard University has created a novel technology for enabling high-throughput proteomics.

Figuring out protein function means seeing how proteins interact with each other, or with small molecules that upset their function. This is not a simple task: For a set of just 200 proteins, his lab must perform as many as 40,000 assays to test all possible pair-wise combinations and identify all homo- or hetero-dimeric interactions.

To do this quickly, efficiently, and with a level of precision, MacBeath has developed a method to perform these assays on a surface the size of a US dime, spotting 1,600 proteins per square centimeter on an ordinary glass microscope slide.

But MacBeath’s is not purely an academic pursuit. He is seeking seed funding for a company he founded, Merrimack Pharmaceuticals, which would use his arrays to screen for drug targets and identify the biological pathways they are involved in. “By screening small molecules using an array of proteins, compounds can be identified that bind to one or a few proteins in the array, but not to others in that array,” he says. He expects to close a first round of financing sometime this quarter.

Meanwhile, his Harvard lab is investigating interactions of several protein families — with 50 to 300 proteins in each — including humans, C. elegans, and yeast. But MacBeath doesn’t just clone full-length proteins. He also isolates individual domains to see which parts of the proteins are responsible for specific interactions and which small molecules change their function. So far, MacBeath’s lab has cloned approximately 240 different sub-domains, expressed and purified in E. coli.

His team is also collaborating with the Naval Medical Research Center malaria program to build microarrays containing all the parasite’s proteins.

One of the biggest challenges is keeping the proteins folded and functional once attached to the glass slide. To keep them in shape, his lab chemically treats the surface with an aldehyde reagent. The aldehydes react readily with primary amines on the proteins to form a Schiff’s base linkage. Covalently attached to the surface, the molecules retain their native conformation. The proteins can attach to the slide in various orientations, leaving different sides of the protein exposed.

The slides are then probed with other proteins, enzymes, or small molecules. Fluorescence- or radioactivity-based assays identify the interactions, and commercially available scanners visualize the results.

“We didn’t want to be the only lab in the world capable of performing this type of work,” says MacBeath, “So it was important that we use common, existing arrayers and scanners to construct the protein arrays.” Although the lab now uses an Affymetrix GMS 417 Arrayer to spot the arrays from 384-well plates, at first it built a robot from readily available materials and directions from the website of Stanford’s Pat Brown. “In order for academia to perform this type of work, the tools needed to be accessible and cost effective,” says MacBeath. “These sorts of efforts should not be restricted to the industrial world.”

 

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