By Chris Fleck

Dr. Angel Yanagihara deconstructs the furious sting of the most venomous creature in the world.

While many people like to comb the shores and beaches of Hawai’i seeking shells, starfish or colorful sea glass, Dr. Angel Yanagihara, has been walking the same sandy stretches searching for an entirely less common, but nonetheless unique ocean creation.

Guided by moonlight and motivated by scientific research and discovery, Yanagihara – biochemist and assistant research professor at University of Hawai’i – has been in the business of collecting box jellyfish for the sake of unlocking the secrets and makeup of their venom, which if you’ve had the pleasure of encountering, can be a most unpleasant experience. Like many scientific discoveries, the origin of Yanagihara’s research was prompted from personal experience. Her Hawaiian box jellyfish research was initiated by that furious and breath-gasping sensation which occurs when a jelly wraps its tentacles around the skin, discharging its nematocysts – which house the jelly’s potent venom-into the bloodstream in a nanosecond’s time. box jellyfish have been categorized as the most venomous animal in the world, most particularly the Australian box jellyfish (chironex), whose sting can cause rapid cardiac arrest and death.

“After I was stung in July of 1997, I soon saw that nothing had been done in terms of rigorous biochemistry. I wrote a grant (proposal) almost immediately… six months after that, I had my own funds to do research,” says Yanagihara – who gives Hawai’i community foundation many thanks for the initial research support.

To understand the intricate composition of Hawai’i’s box jellyfish venom, Yanagihara needed to return to the ocean to collect enough of these jellies to deconstruct the venom using biochemical approaches. But, since the venom in box jellyfish, compared to that of a poisonous snake or spider, cannot be located in a particular gland, Yanagihara needed to sample from thousands of jellyfish.

“Technically the first steps had to be cell biological approaches, purifying those undischarged stinging cells. I spent a good four years working through the cell biology in order to devise new strategies that had never been done before. We then published a paper reporting new structures discovered in the stinging cells,” adds Yanagihara – who as a four-year-old would log and journal measurements and shapes of starfish she found while her father would fish in her hometown of anchorage, Alaska. Detailed and meticulous microscopy of the jellies cells came next, as Yanagihara, working to pinpoint the composition of the venom, separated the complex solution into proteins, lipids and small molecules. she then used a method of purification to identify the compounds that most affected healthy cells, finding that the fastest-acting toxic agent in the venom was a porin, (a type of protein molecule).

It is this porin which pierces red blood cells, allowing potassium to leak into the plasma, which according to Yanagihara is one of the most damaging activities that can happen within the human body.

Potassium is a key component to the electromotive force necessary for heart functionality and proper operation. Continual potassium leakage can have catastrophic effects on the body. High doses of potassium injected into the bloodstream are at times used in the lethal injections of prisoners on death row.

“The transient high levels of potassium in the plasma will basically disrupt all electrical activity related to the heart. You haven’t damaged the heart, so if you can get that person through that crisis and lower the potassium once again, all systems should be go,” adds Yanagihara.

With a sound understanding behind the biological operation of the box jellyfish’s venom, Yanagihara transitioned her research, questioning how to counteract or restrict this hazardous release of potassium. Through the testing of thousands of different compounds and approaches, Yanagihara discovered that the compound zinc gluconate has a staunching effect, drastically limiting the release of potassium from red blood cells.

Testing her hypothesis on both human and animal blood, Yanagihara has succeeded in creating a novel inhibitor or toxin blocker comprised of a zinc gluconate solution, which can be used on victims of a box jellyfish sting. Her technologies have also been used in the creation of a topical preventative treatment, which she provided as a team member during Diana Nyad’s 2012, 103-mile record-breaking swim attempt from Cuba to Florida.

“[The inhibitor,] which I disclosed to the UH offices of Technology Transfer and Economic Development, is the subject of multiple patent applications and has been licensed by a third party to advance it to a commercial product,” says Yanagihara – who is thrilled to have recently had her research and development published in the peer-reviewed, open access PLOS ONE Scientific Journal.

With positive and proven conclusions from more than 15 years of cellular study Yanagihara isn’t yet through with the box jellyfish. Her constant attention to this prehistoric animal has led her to new research ideas focused on other values the box jellyfish has for medical purposes.

“This porin toxin study is only one member of this complex venom cocktail. The thing is, when you’re looking at a life form that’s 600 million years old, almost all the biochemistry has yet to be written,” says Yanagihara who earned her Ph.D. in the Field of Cell and Molecular Neurosciences from UH Manoa.

From those pesky tentacles, Yanagihara moved upward to the box jellyfish’s eyes, noticing a relation to humans, which could be very beneficial.

“Box jellyfish have eyes such as our own with an iris and retina. They have a very elaborate lens with a protein makeup that’s far superior to our own in terms of its mechanical strength, properties and clarity,” adds Yanagihara – who also notes the principle obstacles to most original research usually stem from lack of funding, a circumstance she would love to see gain more attention on a state level.

“One could easily spend a lifetime studying the various interesting aspects of the biochemistry of this animal. Unfortunately, but fortunately for me, there aren’t many who have direct access to the live animals. Box jellyfish are often seen as a grave nuisance, which certainly in one respect it is, but it is also a great opportunity to discover ancient biochemistry.”