The central theme of Dr. Angel Yanagihara's research program is the systematic biochemical characterization of cubozoan venom. The current focus is on the Hawaiian box jelly Carybdea alata. Close cousins of this box jelly (cubozoan) are the Australian carybdeids that can cause Irukandji syndrome and the lethal chirodropid, the Australian box jelly Chironex fleckeri.

The current research projects include:

  1. Hemolysin
  2. Nematocysts
    1. Ultrastructure
    2. Discharge
  3. Pain Receptors and Venom or TRPV 1 Pharmicophores
  4. Box Jelly/Cubozoan Cardiotoxins
  5. Phylogeny of Cubozoans
  6. Population Dynamics: Invasive species? Nuisance species?
  7. Biodiversity of Cnidarian Venoms
  8. Physalia Flourescent Proteins

List of Patents and Publications

A. Hemolysin

Hawaiian box jelly venom contains an extremely potent hemolysin. Hemolysins are proteins which bind to red blood cells and assemble to form pores through the cell membrane. The pores allow hemoglobin to leak out and extracellular fluid to enter causing the red blood cells distend to form large clear red blood cell (RBC) "ghosts."

The images in Fig 1 were taken at the beginning, middle and end of an 8 minute time lapse movie of crude Box Jelly venom added to healthy human RBCs. In contrast, fish RBCs have nuclei and are far more resistant to the box jelly venom. It takes only 1/1000 the concentration of venom that affects the fish RBC to rupture human RBC!

Read our paper on this venom protein.

B. Nematocysts

Ultrastructure

PCRL nematocyst research includes discharge mechanisms, nematocyst morphology and structural properties as well as cnidome characterization. The cnidome (Fig 3) is the specific set of cnidae that comprise the bio-arsenal of a particular cnidarian member.

Discharge

Several videos were taken using a high speed camera and you can see the result in Fig 2. The high speed camera, capable of 33,000 frames per second, was attached to the lab microscope. A special platinum electrode tentacle zapper was manufactured and settings optimized to allow for a sweep discharge across the tentacle surface of a live tentacle held in place across the sea water filled slide chamber with silk threads.

C. Pain Receptors and Venom

We have discovered that the venom contains novel pain receptor activating compounds (Cuypers et al). One of the principal receptors involved in the detection of heat and pain in skin is the TRPV1 receptor. This receptor specifically reacts to compounds like capsaicin in chili peppers. This discovery explains the burning pain sensation after a sting.

We are now working on indentifying the specific compounds in the venom that activate the TRPV1 receptors.

Visit our patent and publications page to learn more about pain receptor research and current related patents.

D. Box Jelly Cardiotoxins

Cardiac effects from cubozoan stings range from rapid cardiac arrest after the sting of the Australian Chironex fleckeri to slow onset prolonged "Irukandji" syndrome catecholamine excess related cardiac effects. Stings of the Hawaiian box jelly have been linked to Irukandji syndrome. We have identified several cardio-active compounds in the venom and are working now to characterize the mechanisms by which these affect the heart.

Read the journal article here.

E. Phylogeny of Cubozoans

Phylogeny is the study of the genetic relatedness of organisms. Interestingly while it is the most infamous, Carybdea alata, or the Hawaiian box jelly is not the only cubozoan in Hawaiian waters. We are actively engaged in collecting different cubozoan members in collaboration with Dr. Allen Collins at the Smithsonian museum to determine the relatedness of these different box jellies to to other cubozoan species in Australia and around the world.

F. Population Dynamics: Invasive species? Nuisance species?

One question asked by many folks in Hawaii related to the box jelly is, "Where did they come from? I don't remember these as a kid." There are specimens from the late 1800s so it appears that these box jellies may be endemic. This is reasonable given the fact that they are a pan-tropical species, that is, they exist globally along the tropics. Still the numbers have dramatically increased over the years. Each lunar cycle over the past 12 years, PCRL lab members go out from about 2AM until 6AM to count and collect beached box jellies in "control" areas of Waikiki. We provide these data to Honolulu Ocean Safety to report to the press and allow for beach advisories when numbers reach over 100 animals per 100 yards of beach front.

G. Biodiversity of Cnidarian Venoms

It is not clear how many of the diverse set of bioactive compounds which make up a particular cnidarian venom are specific to each species of coral, sea anemone, or jellyfish versus how many of these compound are common constituents of the entire phylum. To address this question, we are conducting systematic biochemical comparisons of the major constituents that we discover in Carybdea alata venom.

The presence of a common venom "ingredient list" would be good news from the standpoint of developing better sting treatments.

H. Physalia Flourescent Proteins

This year's Nobel prize was given to a researcher involved in the development of Green Fluorescent protein as a research tool. The local Pacific blue bottle or Physalia utriculus contains remarkably far red shifted fluorescent protein.

rbc1

rbc2

rbc3
Fig. 1 The above images were taken at the beginning, middle and end of an 8-minute time lapse movie of crude box jelly venom added to healthy human RBCs. Watch the video.

nematocyst_discharge
Fig. 2 Still image of a sweep discharge across the surface of a live tentacle. Still image taken from a video taken using a high speed camera. Watch the video.

nematocysts
Fig. 3 Cnidae types ( Möbius, K.A., 1866. Ueber den Bau, den Mechanismus und die Entwicklung der Nesselkapseln einiger Polypen und Quallen.— Abhdl. naturw. Ver. Hamburg V(1): 1-22, pls. 1-2.)