More than a decade ago at UT Southwestern, scientist Steven McKnight chased a compound that turns stem cells into beating heart muscle.
That hunt led him — and Dirk Görlich of the Max Planck Institute for Multidisciplinary Sciences in Germany — to a startling discovery: some proteins carry low-complexity domains, meaning they don’t always snap into a rigid shape, as long assumed. For that work, the scientists have won the 2025 Albert Lasker Basic Medical Research Award and its $250,000 prize, which will be split between them, the Lasker Foundation announced Thursday.
Often dubbed America’s Nobels, the Lasker Awards spotlight foundational discoveries that improve human health and the public’s understanding of science. James Chen, a professor of microbiology at UT Southwestern, received the same Lasker for medical research last year for discovering an enzyme that helps the immune system detect when wayward DNA gets inside a cell.
In announcing the awards, the Lasker Foundation said McKnight and Görlich “transformed our understanding of a fundamental aspect of biology.” McKnight said in an interview that his and Görlich’s work opens new lines of inquiry — from the biology of longevity to potential strategies against neurodegenerative diseases such as Alzheimer’s.
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‘Ugly ducklings’
A small fraction of our DNA makes proteins — the molecules that relay signals, drive metabolism and give cells their shape. Most proteins, McKnight said, are “very complicated, long strings of 20 amino acids and they fold up into beautiful structures.”
For six decades, biology leaned on a simple rule: the amino-acid sequence determines the 3D fold, and the fold determines the protein’s job.
UT Southwestern professor of biochemistry Steven McKnight poses for a photo at his laboratory at the UT Southwestern Medical Center, Sept. 3, 2025, in Dallas.
Chitose Suzuki / Staff Photographer
That framework also explains patterns across proteins: Those that share a fold tend to prefer similar binding partners. Scientists group them into families on that basis, and family members usually carry out related tasks in the cell and across the body.
So when McKnight found proteins that don’t follow this rubric — what he affectionately calls “ugly duckling” proteins — he was surprised.
The road to discovery began a dozen years ago when a colleague of McKnight’s at UT Southwestern stumbled upon a mystery: a chemical that flipped embryonic stem cells into cardiac muscle. The reason behind that process wouldn’t reveal itself, so the colleague passed the puzzle to McKnight. To figure out what was going on, McKnight dunked the compound into a test tube with bits of cell and saw the molecule was a social butterfly — clinging not to one protein but to about 300.
“This is idiotic, this can’t be interesting at all,” McKnight said of the finding. “But sorting out how [that chemical] worked, how it brought down those 300 different proteins, that is what busted the whole thing open.”
McKnight and his then-collaborator noticed these proteins latch onto RNA, the cell’s working copy and courier of genetic instructions. Another pattern jumped out: long stretches that reuse the same few amino acids again and again.
Those repeating stretches, called low-complexity domains, have been known for years; roughly 20% of human proteins carry them, McKnight said. For a long time, though, they were dismissed as floppy and functionless — basically junk.
McKnight first happened across these proteins about 20 to 30 years ago with another scientist at Harvard, he said. “We discovered these really weird proteins, but we couldn’t figure them out,” he said. “Fast forward to this discovery I made with this chemical, and I was dealing with exactly those proteins.”
The next generation
Since then, McKnight and Görlich have shown that proteins with low-complexity domains help arrange the inside of a cell. They do so by forming short-lived structures that let proteins gather, do their job and peel apart when they’re no longer needed.
That quick-release chemistry may explain why proteins misfold and clump — a hallmark of diseases such as Alzheimer’s, Parkinson’s and Huntington’s.
UT Southwestern professor of biochemistry Steven McKnight speaks to The Dallas Morning News in his office at the UT Southwestern Medical Center, Sept. 3, 2025, in Dallas.
Chitose Suzuki / Staff Photographer
With age, it appears these shapeless proteins can change from being loose and dynamic to long, stable chains, like a pearl necklace. In some neurodegenerative disorders, gene mutations cause the misfolding; in others, the trigger remains unclear.
“As you get older and older, there’s a propensity for this to happen,” McKnight said. “So what is associated with aging that allows the aggregation of these proteins?”
Scientists have only begun to scratch at the surface of that question, McKnight said. “To sort this out and to dig really deeply, it’s going to take another 10, 20 or 30 years of people having the fortitude to dig in and understand each [of these proteins] one at a time. There’s not going to be a simple way that everything’s solved.”
At 76, McKnight said he’s leaving the next advances to younger scientists. In the meantime, he’s rather nonchalant about winning a Lasker.
“It’s really wonderful, you get to be king for a day,” McKnight joked, though he was quick to cast the award as a reflection of the area’s appetite for science: “The fact that the Dallas community has supported crazy scientific discovery is wonderful,” he said. “It’s a huge privilege to have been supported.”
Miriam Fauzia is a science reporting fellow at The Dallas Morning News. Her fellowship is supported by the University of Texas at Dallas. The News makes all editorial decisions.