A tale of cacao, birds and the ‘power of emerging model systems’

Tracing the genetic process through which parakeets produce either yellow or blue feathers has given Stanford scientists insights that could help them uncover other biochemical pathways.

- By Nathan Collins

Researchers traced blue budgies’ color to a variation in a protein called MuPKS.
Aimee Wang

If you have ever wondered why some parakeets are green and others are blue, Stanford researchers now have an answer for you.

And, the scientists say, the techniques they developed in the process could one day lead to the discovery of new chemical compounds or biomolecular processes that could impact human health.

The endeavor began over dinner, with a discussion of chocolate — specifically, the domestication of chocolate’s main ingredient, cacao. Thomas Cooke, PhD, then a graduate student in genetics, had been working on tools to study “non-model organisms,” — plants and animals that get less attention than lab rats, fruit flies or baker’s yeast — despite the potential for yielding important scientific insights. Cooke had been working on cacao, but he said the project had “fizzled,” and he was looking for what to do next.

He was discussing his situation at a Palo Alto diner with biochemistry graduate student Kathleen Xie, who mentioned a peculiar trait of the budgerigars she’d raised growing up: wild budgies are green and yellow, but others have been bred since the 19th century to be blue and white — and no one knew exactly how, on a genetic or molecular level, that happened.

Cooke, Xie and colleagues set out to figure out what was in some ways the perfect test case for the methods Cooke had been working on. It had been known for years that wild budgies’ color came from a yellow pigment the budgies themselves produce, and it had been known even longer that their color was a Mendelian trait; that is, budgies either made the yellow pigment or they didn’t. It should therefore be straightforward, if not exactly easy, to track down the gene responsible for determining budgie color.

A colorful quest

Working with Stanford ChEM-H’s 1-year-old Metabolic Chemistry Analysis Center and researchers from around the chemical and life sciences — and members of the American Budgerigar Society and the Budgerigar Association of America, who provided samples and advice — Cooke tracked blue budgies’ color to a gene encoding a protein they dubbed MuPKS, for Melopsittacus undulatas polyketide synthase. (Melopsittacus undulatas is the budgie’s binomial name.) A change to just one amino acid in MuPKS, the researchers found, stops budgies from producing yellow pigment, revealing an underlying blue color in the birds’ feathers. To confirm those results, the team next transferred the MuPKS gene into baker’s yeast and showed that the yellow variant turned yeast yellow, while the other variant had no effect on color.

Their findings were published Oct. 5 in Cell. Cooke, who will soon begin a postdoctoral fellowship at the Massachusetts Institute of Technology, is the lead author.

Even if parakeet color itself doesn’t turn out to be the most interesting subject scientifically, the study is harbinger of things to come, said Carlos Bustamante, PhD, professor of biomedical data science and of genetics and one of the paper’s senior authors.

“What Thomas conceptually demonstrated was we could go into any organism” and learn something interesting and useful about its biochemistry, Bustamante said.

In the future, the techniques Cooke developed — and the ever-declining cost of genetics research in general — could help scientists look at many different plants and animals at once, increasing the likelihood someone will find the next key medicinal compound or biochemical pathway sooner rather than later. “It really demonstrates the power of emerging model systems,” Bustamante said.

“To me, the highlight of the story is Tom Cooke,” said study co-author Chaitan Khosla, PhD, professor of chemistry and of chemical engineering and director of ChEM-H. Cooke and his work, Khosla said, exemplify a new approach to life sciences that bridges work in genetics, biochemistry and other fields.

Additional Stanford co-authors include Curt Fischer, PhD, research engineer; former graduate student James Kuo, PhD; Elizabeth Doctorov, a high school intern at the time of the research and now a sophomore at UC-Berkeley; and Ashley Zehnder, DVM, PhD, research scientist.

The study was funded by the National Institutes of Health (grants T32HG000044, T32GM007276, R01AR47364 and AR 60306).

Stanford’s departments of Genetics, of Biochemistry, of Biomedical Data Science, of Chemical Engineering and of Chemistry also supported the work.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.

2024 ISSUE 1

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