It was June 12, 1979, and the mice in Baldomero Olivera’s lab were behaving strangely. Some were climbing their cages, or racing from one corner to another. Others couldn’t stop scratching and grooming themselves. And now, another group had started to shake uncontrollably.
The quaking mice were in the care of Michael McIntosh, a fresh-faced 18-year-old working in the lab his first summer out of high school. McIntosh carried the mouse cage to Olivera’s office and showed him what was happening.
Normally, the Filipino biochemist would have said something encouraging, along the lines of “that’s fantastic” or “terrific.” But that day, he recollects, he was too stunned by the turn his work was taking for his usual words.
The mice were shaking because of shaker toxin, a chemical component of a deadly venom. Venom was the reason for all the chaos unfolding in Olivera’s University of Utah lab. Each mouse had been injected with a different venom component, and each component was having a different effect.
That was the part that so surprised Olivera. Until that summer, his team had been injecting the venom components into mice via their abdomens and had observed the same outcome—paralysis—every time. But when they switched and injected the components directly into the animals’ brains, a slew of bizarre outcomes ensued.
“Suddenly, the whole game changed—we could see we were dealing with a hundred different components with many different mechanisms,” Olivera says.
His quest to understand what each mechanism does to the body, and how it does it, would profoundly influence the field of neuroscience and help bring relief to thousands of chronic pain sufferers. It would also take Olivera’s research circling back to his childhood, when his interest in the natural world and science was sparked, first on the beach and then in the classroom. Today, as an HHMI professor Olivera is bringing his inexhaustible love of science to young students, in hopes of sparking that same sense of wonder in them.
From Shells to DNA
Olivera—nicknamed “Toto” by a cousin who couldn’t pronounce the Filipino pet name “Totoy”—can’t talk about his past without talking about shells. In the seafood markets of his native Philippines, some shells were sold by the kilo. Others, freshly dredged from Manila Bay, sat in enticing piles, waiting to be crushed and spread on the shell tennis courts of Manila. And wherever they were, they drew Olivera. He spent hours searching for shells, collecting and classifying them, and reading everything he could about them. One shell in particular—the shell of the fish-hunting cone snail—captivated him.
“That was a big prize—it was bigger and more colorful than any other,” he says.
Olivera soon learned that the shell isn’t the only extraordinary thing about cone snails. These meat-eating mollusks come equipped with deadly weaponry: they use a harpoon-like tooth to spear and inject prey with paralyzing venom, and then reel the victim in to devour it. One species of cone snail, Conus geographus (the geography cone), produces venom so powerful that less than half a teaspoon could kill a person.
|Australia's beautiful but deadly cone snail.|
Although Olivera never stopped collecting shells, he eventually set his childhood interest aside, seduced by the budding field of DNA research and the opportunity to pursue graduate study at the California Institute of Technology in Pasadena.
At first, he struggled to adjust. “I didn’t know anybody, and everyone was working in the labs until late at night,” he says. “I thought the place was a kind of monastery.”
But he soon found his way into the lab of molecular biologist Norman Davidson, a DNA pioneer who inspired Olivera to trust in his own abilities and take chances with his work. After Olivera completed his PhD, Davidson advised him to accept a postdoctoral position at Stanford University, where more cutting-edge DNA research was underway. There, Olivera found another mentor and collaborator, biochemist Robert Lehman, who would become a lifelong friend.
Right away, Lehman was struck by Olivera’s enthusiastic and unusual approach to doing science. “He was very original, very creative in his scientific thinking,” says Lehman, now a professor emeritus at Stanford. “He’s probably one of the most imaginative scientists I know.”
Lehman had begun to explore DNA recombination—the process that shuffles genes into new combinations during cell division—just before Olivera arrived in his lab. Recent experiments had shown that recombination involves cutting and rejoining of DNA fragments. “I decided I wanted to understand how the rejoining happens,” Lehman says. “I suggested this to Toto, and within six months he had discovered an enzyme that could join two DNA molecules to each other.”
Olivera was among the first to isolate and purify a DNA ligase, a kind of enzyme that can knit together pieces of DNA. A significant discovery, it drew attention from potential employers across the country, Lehman recalls. Yet Olivera had always planned to return to the Philippines. So when Kansas State University offered him an appointment enabling him to spend four months of the year in Kansas and the remainder at the University of the Philippines, Olivera jumped at the chance.
Venom as Medicine
Back in the Philippines, Olivera faced a dilemma. The university in Manila didn’t have the equipment or funds for his DNA research. It became clear that he would be able to continue that work only while in the U.S. and would have to find another scientific mission for his lab in Manila.
Olivera found himself thinking about the colorful cone snail shells he’d collected as a child. He had always wondered what made the snails’ venom so deadly. What if he applied the techniques he’d learned from Davidson and Lehman to find out?
In a bare laboratory with minimal resources, Olivera got to work. He began to purify the geography cone’s venom, teasing apart the chemical compounds and mechanisms that make it so lethal. He found that the venom not only shuts down communication between nerves and muscles, as does the toxin in some snake venoms, it also wipes out electrical signaling in the nervous system, like the toxin in pufferfish.
“It’s a one-two punch of venom—like being stung by a cobra and eating a lethal dose of pufferfish at the same time,” Olivera says.
He discovered that the snail venom’s chemistry is unusual. The venoms of cobras and other snakes are complex, containing large proteins made up of scores of amino acids. But the cone snail venom contains only relatively small and compact proteins, called peptides, with 10 to 30 amino acids.
The finding intrigued Olivera, but it didn’t lure him away from his DNA research. “I didn’t think I’d be working on cone snails for very long,” he says—just long enough to get the equipment needed to work on DNA.
That plan changed when Olivera’s life took an unexpected turn in 1973. Amid the political upheaval of Ferdinand Marcos’ rule, Olivera feared for his family and found dwindling support for his science. So he decided to settle in the U.S. full time with his wife and two young children, and taking a faculty position at the University of Utah in Salt Lake City.
Once there, he kept his cone snail research as a side project, mostly assigning students to purify the venom’s components and study their effects on mice. It was then that two young researchers—McIntosh and 19-year-old Craig Clark—re-ignited Olivera’s interest in the cone snail and its secrets.
“Craig looked at what we were doing and said, ‘You know, I don’t think you’re doing this right,’” Olivera recalls. Clark’s idea was to inject the venom components directly into the animals’ brains.
Olivera found the suggestion “appalling,” but he was willing to try it anyway. They quickly discovered that each peptide had a different effect, which helped with the naming of each peptide. For example, the “sluggish” peptide slowed mice down; the “sleeper/climber” peptide put young mice to sleep but made older ones hyperactive.
And the shaker peptide, first discovered by McIntosh, took on a life of its own. The peptide stopped the flow of calcium that allows communication between nerves and muscles, according to findings by another Olivera collaborator. Blocking these “calcium channels” enabled neuroscientists to study how the nervous system talks to the body—something that had not been possible before.
Olivera wondered if that blocking action could have therapeutic effects. He and his team collaborated with George Miljanich, first at the University of Southern California and later at the biotech company Neurex, to explore the shaker peptide’s pharmaceutical potential. They discovered that, in mammals, the peptide affected some but not all calcium channels, and that it specifically disrupted the channels associated with pain. It proved to be a powerful painkiller—up to 1,000 times more potent than morphine. A synthetic form of it is now a drug sold as Prialt, commercially developed by Elan Pharmaceuticals and approved in 2004 for severe, hard-to-treat pain.
A Constellation of Targets
Thirty years after their collaboration began, McIntosh is a professor of psychiatry and biology who leads his own lab at the University of Utah, and he and Olivera continue to work together. Over the decades, they have deciphered that the cone snail’s venom works through what Olivera calls “cabals”—chemical combinations intended to act on several biological processes in the snail’s victim all at once.
“If you want to get rid of the HIV virus, you need to use a combination of pharmacological agents,” Olivera says. “Cone snails basically use the same principle—they don’t do things with just one drug. They aim for a constellation of targets.”
Olivera and his team are using a new approach to drug development—he calls it “constellation pharmacology”—that exploits these cabals, mixing and matching their components to treat a host of other ills, from epilepsy to Parkinson’s disease. Their discoveries wouldn’t be possible without Olivera’s openness to new ideas, McIntosh says.
“Toto is always willing to listen,” he says. “No matter what degree a person holds or what they do, he believes they’re worth listening to.”
Today, turning the cone snail’s poison into medicine dominates the work in Olivera’s lab. But he’s also making time for a different kind of experiment—one that, like his cone snail work, traces its roots to his childhood.
At age seven, Olivera spent a year in San Francisco while his father served as a press attaché in the city’s Philippine consulate. One day, Olivera’s teacher led the class in a series of experiments, mixing water with salt and other crystals to teach the second-graders about solubility.
He still recalls his wonder at the fact that some substances dissolve, and some don’t. Long before he fell under the spell of shells and venoms, he says, “that was the root of my wanting to become a scientist.”
Now Olivera works to bring that love of science to other young children. With support from an HHMI professor grant, he has developed a science education program—the Chemistry to Biodiversity project—that brings hands-on science to second- and third-graders who wouldn’t otherwise have the opportunity to experience it. The program pairs the children with college students, who serve as mentors, and covers a series of experiments that link the physical sciences to biodiversity and the natural world. In fact, it includes the very same solubility experiment that sparked Olivera’s imagination as a child.
After the 2013 earthquake and typhoon in the Philippines, Baldomero Olivera began a mission to help rebuild the Philippine Science High School.
The program has been implemented in some Salt Lake City schools and in the Philippines, where at least four large provinces have incorporated it into the standard K-12 curriculum. In the wake of Typhoon Haiyan in 2013, the deadliest Philippine typhoon on record, Olivera’s efforts have expanded to provide lab equipment, computers, and other supplies for schools being rebuilt in devastated areas. The need and distress he has seen there galvanizes him to do more and more to help.
“You realize all the other problems that need to be creatively addressed,” he says. He doesn’t claim to have the answers, but he hopes his passion and creativity can contribute to the solution. They haven’t failed him yet.