Brian Liau didn’t want the standard off-white. He wanted bold, bright, and unexpected.
To work out his new lab’s paint scheme, Liau came up with a systematic — or, one could say, scientific — process. He left patches of various paint colors on the walls for days to assess the long-term impression they made. He eliminated options, selected his favorites, and opened the final decision to a lab-wide vote. Now, morning-glory blue blooms in the hallway, sunrise orange enlivens the tissue-culture room, and a soft spa green pops up wherever an accent is needed.
But within those sunny walls, Liau, an assistant professor of Chemistry and Chemical Biology, investigates a dark problem: how to beat cancer, in particular acute myeloid leukemia (AML), which the American Cancer Society predicts will kill 11,000 people in the U.S. in 2019.
Two out of three AML patients achieve remission with chemotherapy. To help patient No. 3, drug developers are trying a different tack. Since AML starts in the bone marrow when mutated genes fail to prevent blood cells from replicating again and again and growing into tumors, new drugs aim to reverse the mutation’s effects, reclaim hijacked cells, and halt growth. But these drugs don’t always work.
Now, in a paper published in Nature Chemical Biology, Liau explains how certain AML drugs work.
Using a new technique he calls CRISPR-suppressor scanning, Liau combines CRISPR scanning, a form of gene editing, with small-molecule profiling (a way to screen numerous drug molecules in one go) to investigate how current drugs fit into the nooks and crannies of the malfunctioning genes they target. He and his team systematically identify mutations in LSD1, a critical protein in AML, and in doing so expose details about the relationship between cells and the drugs used on them that may one day lead to faster, more targeted treatments not just for that third patient but for all cancer patients.
Designing a drug is far more complicated than designing a new lab space. But, just like blue can be periwinkle, sky, or sapphire, each drug molecule can have many variations. Developers tinker with these to see if slight alterations — a bump on this side, a hole on the other — make their treatments more or less effective.
“As chemists, we have the ability to make nearly anything,” Liau said. “Now, we have the unprecedented ability to systematically change protein structure directly in cells.”
Epigenetic changes occur when genes are switched on or off by environmental factors — often things like diet, exercise, and chemical exposure. But in the subtype of AML Liau and his colleagues looked at, mutated genes trigger epigenetic shifts, reprogramming blood cells to grow out of control. Enzymes often regulate the conversation between genes and the cells they supervise, but in this case these proteins malfunction.