Releasing the Hydra with Rafael Yuste

Rafael Yuste woke up in his bedroom. It was early on a Sunday morning at the end of March 2019. Manhattan was quiet outside his windows. He had been dreaming of Sydney Brenner, sitting face to face with the Nobel-Prize-winning biologist. Brenner was speaking about Hydra as a model in neuroscience but also chiding Yuste, telling him to forget funding concerns and focus on the things that truly matter in science.

He was so shaken by the dream that his wife woke up, too. A few days later, Yuste was reading the news online when he saw that Brenner had died—on 5 April.

It’s not surprising that Brenner would be on Yuste’s mind, whether before, near or after Brenner’s death. Yuste considered him to be his “North Star,” and it was Brenner who initially guided Yuste toward a life in research and then, after a setback, pointed Yuste toward Hydra. “I consider him maybe the most important influence in my life as a scientist,” says Yuste, 61, professor of biological sciences at Columbia University.

Yuste’s attention and lecturing have expanded Hydra’s use in neuroscience. The BRAIN Initiative recently included Hydra as a model organism, placing it alongside canonical model systems for neuroscience, such as mice and Caenorhabditis elegans, says Jacob Robinson, professor of electrical and computer engineering at Rice University and a collaborator of Yuste’s. This inclusion would have been “shocking 10 years ago,” he says.

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uste grew up in Madrid. His father was a lawyer, and three of Yuste’s siblings now work in law. His mother had wanted to go into medicine, but “women didn’t become doctors” in Spain then, Yuste says, and instead she opened a blood testing lab. It was there that Yuste got a taste of science—counting, by hand, white blood cells under a microscope.

As a teenager, he read the autobiography of the neuroscientist Santiago Ramón y Cajal, understanding that, as a fellow Spaniard, he was living in the famous scientist’s “towering influence,” Yuste would later write. But his mother pushed him to become a doctor, so Yuste attended medical school at Universidad Autónoma de Madrid, beginning in 1981. In his third year, he got curious about the research side of medicine. He wrote a letter to Brenner, then director of the Laboratory of Molecular Biology at the University of Cambridge, and volunteered to work in his lab over the summers. “To my surprise, he wrote me back,” Yuste says.

He spent two transformative summers at Cambridge, working most closely with Leslie Barnett studying bacteria. One night in the lab she told him about research she had done with Francis Crick and Brenner, determining that the genetic code consists of three base-pair codons. It was one of the “most elegant experiments” he had ever heard of, he wrote years later, and he abandoned thoughts of becoming a medical doctor. He finished his medical degree and asked Brenner where he should study for his Ph.D. Brenner told him to “go West,” Yuste says, to Torsten Wiesel at Rockefeller University.

Yuste joined Weisel’s lab in 1987 and worked with postdoctoral researcher Larry Katz. They used calcium imaging to show groups of neurons firing together in the developing cortex of several animal models. Their abstract on this work at the 1989 Society for Neuroscience meeting caught the attention of David Tank, then at AT&T Bell Labs in New Jersey. Tank offered him a postdoc, and for years Yuste worked at Bell Labs, collaborating with Winfried Denk to image calcium in dendritic spines.

In 1996, Yuste joined Columbia University’s biological sciences department as assistant professor. He spent time with the physical sciences and engineering groups, and also with the school’s neuroscience community. He reviewed dendritic spines and their morphology after long-term potentiation and used two-photon calcium imaging to research spontaneous activity of neuronal populations in the mouse visual cortex. By 2005, his career had so flourished that he was named a Howard Hughes Medical Institute (HHMI) Investigator. The award came with an “almost unlimited amount of funding to do whatever I wanted,” Yuste says. So much money, he says, he returned his existing U.S. National Institutes of Health (NIH) grants, because he felt it was unfair to “double dip.”

But when Yuste came up for HHMI review in 2013, he explained to his review panel that he wanted to test a theory that the cortex was actually a neural network. The idea had been planted, Yuste says, during his days at Bell Labs, where he became familiar with the work of John Hopfield, the physicist who would win the Nobel Prize in 2024 for enabling machine learning with artificial neural networks.

A panel member stood up to disagree with Yuste, and about a week later Yuste received a letter from HHMI informing him that he would not be renewed. Essentially, “they cut me off,” he says. (HHMI, through a spokesperson, told The Transmitter it does not comment on personnel matters.) He had tried for something “too visionary” for HHMI, Yuste says, and “obviously it did not work.” He wrote 10 grant applications that year and “luckily regained NIH funding.”

The HHMI nonrenewal was still on his mind when Brenner came to Columbia in September 2013 to give a talk. Over lunch, Yuste told Brenner he had been unable to get HHMI to support his neural network idea.

“You will never convince them,” Brenner told Yuste, because science accepts new ideas slowly. He suggested that if Yuste wanted to study neural networks, he should go back to basics. Brenner’s 2002 Nobel Prize came from his work establishing C. elegans as a model organism, and he pointed Yuste toward another simple model: Hydra, first studied in the 1700s.

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ydra vulgaris is a cnidarian, or jellyfish relative, that represents one of the earliest evolved nervous systems. Its cylindrical body contains two layers of tissue and a nervous system that ranges between 200 and 2,000 neurons, depending on the size of the Hydra. The creatures locomote by somersaulting, moving head to foot, end over end. Their stem cells constantly renew, and thus the animal doesn’t age. They can be fed brine shrimp rinsed in freshwater and can be kept in small spaces—in Yuste’s lab they live in culture wells, in an incubator beneath a lab table.

After speaking with Brenner, Yuste asked his graduate student Christophe Dupre to look into Hydra. Dupre went to the University of California, Irvine to visit Robert Steele, who had been studying Hydra since the 1980s. The first transgenic Hydra was created in 2006, by Thomas Bosch and his collaborators. Yuste and Dupre wanted to build on that (and on critical work done in Steele’s lab) and make the animal more useful for neuroscience. They created a transgenic line that expresses a calcium indicator called GCaMP6s in neurons. The idea was to allow researchers to see “the activity of every neuron in an animal during behavior,” Yuste says.

Dupre went back to Irvine to show Steele details on the transgenic Hydra. He pulled up a video of the animal on his laptop, its neurons flashing away. “My jaw dropped,” Steele says. “This is the kind of thing you thought we would just be dreaming about forever, and here it was reality.” Yuste and Dupre published the work in Current Biology in 2017. The editors put it on the cover.

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or more than 135 years, biologists and neuroscientists have gathered at the Marine Biological Laboratory (MBL), in Woods Hole, Massachusetts, to study and exchange ideas. Less than a mile’s walk from the lab, and alongside the Church of the Messiah, is the Woods Hole Village Cemetery. Nobel Prize winner Albert Szent-Györgyi is buried there, and so are parthenogenesis researcher Jacques Loeb and Nobel winner Otto Loewi, among many other scientists. Yuste was invited to lecture on Hydra at MBL in 2014, and he returned the next year to teach a summer course. In 2017, his third year teaching the course, he packed equipment and an incubator into his car and relocated his lab and team to MBL for the summer.

The lab became a “watering hole” for Hydra researchers in the United States, at the time only enough people to fit at a “full picnic table,” Yuste says. Steele came to Woods Hole. So did Adrienne Fairhall, professor of physiology and biophysics at the University of Washington. Eventually, Yuste and Fairhall, with others, would create an algorithm to track the position of a neuron using calcium imaging in freely behaving animals, with Hydra as the test case. Today there are about 10 different labs looking at Hydra, totaling roughly 40 researchers, Yuste says. 

Yuste’s work on the animal has expanded as much as the field. He never had much interest in peptides, but while Yuste and his postdoc Wataru Yamamoto were studying somersaulting in Hydras—curious as to “how the hell does this nervous system with 300 neurons” achieve such complex behavior, Yuste says—they discovered that rhythmic potential neurons are activated by a neuropeptide called Hym-248 before the somersaulting begins. Now Yuste believes neuroscience has “underestimated the importance of chemical signaling.”

That “how the hell” kind of inquisition is a hallmark of Yuste’s, as is his enthusiasm. Fairhall says Yuste is “one of the more complex people I know in neuroscience,” pointing to his “brilliance” and a reputation for “creativity and innovation,” but also saying he can be demanding and “a bit irascible.”

Yuste is aware of this. Partly it’s in his nature to be “frank,” he says, but he trained in medicine and saw that doctors sometimes need to deliver woeful news without sugarcoating, and he employs the same style with his students. But beyond that, “the worst thing” a principal investigator can do to a trainee is avoid pointing out mistakes, he says, “because that will hurt his or her career.”

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hough losing the HHMI award in 2013 felt like a setback at the time, in some ways it gave Yuste “more freedom,” he says. He had room to get involved in science policy, based on his work with the Brain Activity Map Project, and that eventually led him to an adviser position for the White House’s Brain Initiative. He had room for advocacy, too, such as helping get the world’s first constitutional amendment concerning neurorights passed in Chile.

Yuste thinks that “what happens today is a product of what happened in the past,” and that if you want to understand both science and the greater world, “then you better look back.” This is partly why, starting in 2015, each summer he brought MBL’s Neural Systems and Behavior course students and Hydra lab members to the Woods Hole Village Cemetery to see the graves of scientists who had come before them; in 2018, members of his Hydra lab created an interactive map of the gravestones.

Yuste also sees himself as part of a scientific lineage. It includes Ramón y Cajal, the famous Spaniard; Crick and Barnett, with their “elegant experiment”; and his mentor, Brenner. All have passed away, and all had something in common scientifically. “They loved methods,” he says, and they knew that methods are what drive science forward. There is a quote of Brenner’s that Yuste keeps handy: “Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.”

“Cajal was like that,” Yuste says. “Crick was like that; Brenner was like that. I belong to this type of scientist, and I’m just one more.”