Focus on Research: Scientific Freedom Leads to Publication in Nature.

Silvestre Alavez and Gordon LithgowWhen Buck Institute Staff Scientist Silvestre Alavez, PhD, looked at a common yellow laboratory dye three years ago and wondered if it might be able to enhance lifespan, he decided to run a few private tests before mentioning the quirky idea. Luckily, he works in the Gordon Lithgow lab, where side experiments – nicknamed “pocket projects” – are encouraged. Such support and freedom are essential to discovery, said Alavez, a native of Mexico who has expertise in biochemistry and neurobiology. “Gordon is an amazing boss -- open to ideas, always encouraging every person in the lab to develop new areas, new ideas, and then saying, ‘Don’t just think about it – do it.’”

The work to prove Alavez’s concept, which he disclosed after initial positive experiments, was steady. “There was no eureka moment,” Lithgow said. “It was day-to-day work with rising excitement. Silvestre carried the research by himself for a long time with a little help from graduate student David Zucker.” As work advanced, other colleagues joined in. Last summer it became a team effort as Lithgow directed more lab resources to the project.

The amazing result – that the dye Thioflavin T (ThT) acts like a wonder drug to extend lifespan and slow Alzheimer’s-like symptoms in nematode worms – was recently reported in the prestigious science journal Nature. The discovery highlights a process called protein homeostasis, the ability of an organism to maintain the proper function of proteins through maintaining synthesis, shape and degradation. The research could open new avenues in the quest for medicines that promote healthy aging. Alavez is already working with collaborators who are testing the compound in mice bred to develop amyotrophic lateral sclerosis (Lou Gehrig’s disease) and Alzheimer’s disease.

ThT is used in neuroscience labs to detect damaged proteins in Alzheimer’s. Damaged, or aggregated, proteins also are bad actors in other neurodegenerative diseases such as Parkinson’s and Huntington’s. Alavez found that another compound, curcumin, had a positive impact on both healthy worms and worms bred to mimic Alzheimer's. Curcumin is the yellow ingredient in the Indian spice turmeric. "People have been making claims about the health benefits of curcumin for many years,” Alavez said. “Maybe slowing aging is part of its mechanism of action."

Alavez’s belief in his idea and his perseverance were keys to success in the lab, Lithgow said. Perseverance also played a part in publication. Alavez’s first submission to Nature was returned with requests for further information. It would have been easy to send the article to a less prestigious journal, but Alavez and Lithgow decided to conduct more experiments, seek feedback from a new in-house “faculty paper polishing” group at the Buck, and then re-submit to Nature. It took several months. “The temptation was just to get published but we wanted to respond to some great suggestions by Nature referees,” Lithgow said. “It takes patience, money, support, and determination to tough it out with these leading journals.” The research was covered widely in the media, including an article in The New York Times.

Looking ahead, Lithgow observed, “One idea now blossoms into science for scores of people to work on. Our job now is to ask, ‘What do we select?’ It’s tough because choosing one thing means letting go of others. With current funding limits, one lab can’t do everything. Still, it is a privilege to be doing this work. Because of Silvestre’s idea, there is a world of new possibilities.”

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