The brilliance of Fil-Am scientist Baldomero Olivera

Spend some time with Filipino-Americans, and you’ll discover our strong pride in our heritage. We all cheered for Manny Pacquiao every time he stepped into the ring. We recite jokes from Jo Koy’s Netflix special. Sometimes we harmonize with Lea Salonga on A Whole New World. And we’re especially in tune with which celebrities have even the tiniest bit of Filipino heritage (Did you know actress and singer Hailee Steinfeld is part Filipino??)

A career in science is certainly less glamorous than that of red carpet celebrities. A 2021 poll, suggesting that 72% of Americans can’t name a single living scientist.1 Even for Filipino-Americans, with our senses always attuned to others of a similar ethnic background, might struggle to identify a Fil-Am scientist; to be honest, I had a tough time with this.

I don’t always pay attention to the authors of the papers I read. But when I came across a publication by Baldomero Olivera in the Annual Review of Pharmacology and Toxicology, my Filipino-radar started beeping. In this paper / scientific memoir, Olivera describes how he stumbled from a career as a chemist into the world of pharmacology, and ultimately how his findings led to the development of an extremely effective non-narcotic pain killer.

Olivera attributes much of his success in research to his multicultural background. Having been born and raised in the Philippines but partially educated in the United States, by the time he began his own research program, Olivera had by necessity become intellectually flexible. The Philippine educational system, strongly guided by it’s history of colonialism by Spain, Japan, and the US, is strict and teaches a rigid deference to hierarchical authority. The United States, where Olivera earned his PhD, however, carries a different set of individual-centric values. Olivera believes that the difficulty of straddling both of these worlds gave him an advantage in his science.

Additionally, Olivera’s credits creativity in identifying novel angles to help him work around academic roadblocks. After completing his post-doctoral fellowship in Biochemistry at Stanford, he returned to the Philippines to establish his own research program. Intending to continue the DNA synthesis and enzymology work he had began during his American post-doc, he found that his new lab at the University of the Philippines didn’t quite have the same equipment that he was used to. Instead, he pivoted his work to a different project, one that might be less dependent on expensive pieces of technology.

At this point, Olivera meshed his work with his childhood hobby: collecting cone snails.

Taken from https://critter.science/the-deadly-cone-snail/

Nature is full of weird animals, and the cone snail is no exception. Found in tropical waters, these slow-moving sea creatures bury themselves under the warm sand or rocks. Here, they lie in wait until fish swim by. Suddenly, a barrel-like appendage deploys a tiny harpoon laced with neurotoxin, puncturing the victim’s scales. The venom immediately paralyzes the fish - then it’s dinner time for the carnivorous cone snail.

Envenomation by cone snail toxin can be potent enough to kill larger animals, like humans. One particular species, Conus geographus, is also called the “cigarette snail”. As the legend goes, once stung, a person has enough time to smoke a cigarette before they die.

After the venom has been safely extracted from the snail, your typical toxicologist would study the composite “cone snail venom”, which is made up of 100-200 different individual compounds in nature. However, Olivera’s background in biochemistry and naivete in the field, led him down a different angle of study. Olivera was more curious about the individual chemical components of the toxin, most of them being small peptides of fewer than 30 amino acids.

One of the earlier studies in Olivera’s debut into the world of research pharmacology described the effects of omega conotoxins, peptides isolated from cone snail venom. These conotoxins induce paralysis through acting at a molecular target found on the presynaptic side of the motor neurons, specifically the voltage-gated calcium channels. At a healthy neuromuscular junction, depolarization of the motor neuron allows for opening of the voltage-gated calcium channels, allowing entry of calcium ions into the axon terminal. That calcium is needed to bind to a host of proteins called the SNARE complex, which in turn allows vesicular fusion and release of the neurotransmitter acetylcholine into the neuromuscular junction. This chemical signal then activates receptors on the muscle, leading to contraction.

In short, omega conotoxins block the entry of calcium presynaptically, which prevents motor neurons from signaling to the muscle, leading to paralysis. (This research was a collaborative effort between his new lab at the University of Utah and coworkers from the University of the Philippines, where cone snails are common finds in the tropical waters 4.)

The research in omega conotoxins have led to major developments in pharmacology. The most well-known example of conotoxins is the administration of ziconotide for chronic neuropathic pain. Marketed as Prialt, ziconotide is an analgesic that is 1,000 times more potent than morphine, and yet carries no risk for addiction. Ziconotide cannot be taken by the more common routes of administration, such as oral or transdermal. Instead, it must be delivered via an intrathecal injection, where it gets delivered directly into the cerebrospinal fluid.

Best known for it’s uses in treating pain, it is also being tested for application in Alzheimer’s disease and multiple sclerosis.

Olivera’s inspirational story is one of rising above adversity: he describes how his grant applications to study the conotoxins were rejected because he had

”…no expertise in toxicology, no expertise in peptide chemistry, and no expertise in neuroscience…”

And yet, despite this scathing criticism, Olivera today stands as an inspirational figure for Filipino-Americans in science.

Taken from https://www.hhmi.org/scientists/baldomero-m-olivera

AustinBaldomero Olivera, Cone snail, NeurotoxinsComment