Research
Reading risk in the structure of BRCA1
Some inherited BRCA1 changes clearly raise cancer risk. Most are still question marks. Our job is to read the answer in the protein itself.
The question
A test result that says “unknown”
BRCA1 is one of the cell's repair crew leaders: when DNA breaks, BRCA1 helps organize the fix. When an inherited mutation stops it from doing that job, the risk of breast and ovarian cancer climbs. That is why genetic testing for BRCA1 matters — and why an unclear result is so hard. Most of the changes found in BRCA1 are variants of unknown significance: we can see the change, but we can't yet say whether it is harmful. Behind each of those is a person trying to make a real decision.
The way to resolve the uncertainty is to ask a direct question about the protein: with this change, does BRCA1 still work? Because a protein's job depends on its shape, we can answer that by studying structure and function in the lab. We take two complementary approaches.
Approach one
The molecular handshake
BRCA1 can't repair DNA alone. It has to clasp a partner protein, PALB2, through a pair of intertwined corkscrew-shaped helices — a “coiled coil.” That clasp is what brings the rest of the repair machinery to the break. Disrupt the clasp, and repair fails.
We built a fast, inexpensive test that measures the faint pulse of heat released when BRCA1 and PALB2 grab each other, so we can ask of any variant: does it still hold on? After checking the test against changes already known to be harmful, we used it to flag two previously uncharacterized variants that completely break the grip — marking them as likely dangerous. We also found a clean rule: a single “kink” amino acid (proline) collapses the helix and breaks binding anywhere in this region, even away from the contact point. The payoff for patients: this screen runs in about four days, can be performed by undergraduates in an ordinary lab, and could help prioritize which variants need deeper clinical study.
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Approach two
A worm, and keeping the tools honest
BRCA1 has a second job: helping switch certain genes off by tagging the proteins that package DNA. We study this using C. elegans, a tiny worm with its own versions of BRCA1 and its partner. The worm lets us test ideas quickly that would be far harder to test in human cells.
Good science also means checking the tools everyone shares. Many labs rely on a particular worm strain to study these genes — but we found it doesn't behave the way the field assumes. Several of its gene-silencing patterns look normal, and one runs the opposite direction entirely. We published a careful caution so other researchers don't build conclusions on a cracked foundation. It's unglamorous work, and it's exactly the kind of rigor the science depends on.
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How we watch a protein
Seeing shape, and seeing it change
A protein is far too small to watch under a microscope. Instead we read its structure indirectly — measuring how it folds, what it binds, and how a single mutation shifts the picture — with a toolkit of biochemistry and biophysics.
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Every claim above comes from peer-reviewed work you can read yourself.