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Making Waves: Episode 36 (September 30, 2009)

In 2002, a mysterious disease began killing fish at a commercial aquaculture facility in North Carolina. Lots of fish. Over 21,000 striped bass died during the outbreak. At the time, no one knew what caused this massive fish kill. Why did it happen? Would it happen again?

We now know that the culprit behind the fish kills is a type of freshwater algae called Euglena Sanguinea, thanks to research led by the U.S. Department of Agriculture and NOAA back in 2004.

At the time this was a big surprise. Euglena is very well documented. In fact, it’s been known since 1830. It was just that everyone thought that it was harmless. Well, it turns out that, under the right conditions, Euglena can produce a potent, very deadly toxin.

Today we’re going to take a look at a new study led by the same two scientists from NOAA and the USDA from the 2004 breakthrough, and it takes what we know about this toxin one step further – and in a surprising direction.

It turns out the compound produced by Euglena – a compound that can kill fish and mammals in the wild – may not be all bad. The very fact that this compound is so deadly means that, if we can harness it, it may offer new ways to treat human problems.

Could a toxic chemical produced by Euglena, a type of algae known for well over a century – algae that you may have even seen before under a microscope in your High School biology class – someday be used to treat cancer? Stay tuned.

It’s Wednesday, September 30th, 2009, and this is Making Waves from NOAA’s National Ocean Service.

Powerful Fish-Killing Toxin Holds Promise for Cancer Applications

Today we hear from chemist Peter Moeller from NOAA’s Center for Human Health Risk, part of the National Ocean Service’s National Centers for Coastal Ocean Sciences. Peter works at the Hollings Marine Laboratory in Charleston, South Carolina, and he’s one of the lead authors of a new study about this powerful fish-killing toxin that’s slated to appear in an upcoming issue of the journal Toxicon.

Peter leads the Toxin Natural Products Chemistry program. His job is to figure out what’s going on, chemically speaking, when unexplained events happen, like when 21,000 bass mysteriously die in North Carolina. When something bad like this happens in the wild, Peter’s lab gets samples of the bad stuff, and he and his team go to work. The first step is to purify the samples to tease out the active compounds that are causing the problem. Here’s Peter:

”I always call myself to my students kind of an NCIS or CSI type of a program. Something has happened in an event: a mammal die or whatever, and somebody has made an observation that they think the causative agent is this organism or it’s the seawater or it’s the sediment, or it’s tissue of some sort, dirt – it doesn’t matter – they bring that to my lab. Now whatever they bring, this starting material we’re going to work with – this tissue, mud, water, it’s full of tens of thousands if not millions of compounds. The purification process is something that I have to do tease each chemical apart from the other so that I end up with an analytically pure compound.”

The next step is to figure out the molecular structure of a given active compound to see how it works. He said it’s a lot like trying to figure out who a person is through a fingerprint.

”In chemistry, we talk about structure of a molecule and its function. Aspirin works the way aspirin works because of its molecular structure not because it has some sort of inherent activity. That structure, once it gets into a mammalian system such as human, does its job of analgesic or reducing swelling. That structure, then, is what we want to key in on. So, to understand structure, on the one hand, we have to have a three-dimensional picture of that molecule. That in turn will tell us probably, or at least give us clues, to ask questions: how is it working in a mammalian system? Where is it working in a mammalian system? And frankly it tells us a lot about its chemistry. It’s like your fingerprint and my fingerprint. We’re different, and our finger prints are different. Once I have your fingerprint, I know who you are. So from NOAA’s point of view, when there is, say, a shellfish toxin: people eat oysters and get sick. They’ll bring me oyster tissue and ask me: what is it that made these people sick? Well, I need to find out that fingerprint of a molecule because that’s going to be the culprit. It’s looking for the bad guy. At the same time, we then use that fingerprint to develop what we would call detection or monitoring tools. I won’t get too specific, but we have special analytical techniques which will then find that material, that compound, and in matrix where we find it, and then we can alert the public.”

While he and a team of researchers discovered that Euglena algae were behind the fish killings back in 2002, that study only showed that the algae were producing toxic effects – that the algae were responsible for the dying fish. This new study takes it one step further.

”It’s one thing to show that an organism has toxic effects, but one of the things that has to be done is to demonstrate that there is a true toxic entity. That may seem trivial, but it’s not always so easy. In this case, we did find that the organism was producing a chemical that was responsible for the toxic effects.”

That chemical is called Euglenaphycin. So once Peter and his team teased out the toxin and unlocked its molecular structure, they turned their attention to a new type of investigation: looking for ways, as Peter says, to see if this deadly chemical can be turned from the dark side to do good work. What if Euglenaphycin -- this very potent toxin -- could be used to kill cancer cells? If you consider that we use toxic chemicals – better known as chemotherapy - to shrink tumors and kill cancer cells, why not test natural toxins like Euglenaphycin out to see how they work? Many of the natural toxins that Peter looks at in his lab, after all, are much more toxic than the compounds used today for chemotherapy. If they do the job effectively and kill cancer cells, it would take much less toxin to do the job than what we’re now using.

”While we do these things, the highly toxic compounds that we look at, it’s very difficult to describe how much more toxic they are than many of the compounds out there for chemotherapy and things like this. They’re just so much more toxic. But when one stops and realizes that, and I use cancer or chemotherapeutics as a model, these are toxins. And we inject them in the body to help kill cancer cells. Well, as I’ve been working through the years, and you get to see the selective activity that they have, as well as the high activity – many, many, many times more active than the current pharmaceuticals that we’re using today – why can’t we at least try to push them into, again, as an example, cancer therapy. Because if they’re so much more toxic, we don’t need as much of them conceptually to do the same job, and that in turn should help us reduce side effects if we don’t have to be putting so much into our systems for that. So that’s been a big push of ours, that as we do NOAA’s mission finding these compounds that are causing the deleterious effects that we see, and then turning around, turning them to the good side.”

How does Peter figure out if a toxin might have a use in treating cancer? Samples of mammalian cells are tested out to see how they interact with the potent toxins identified in the lab. If the mammal cells die, it’s an indication that the toxin may have at least some cancer-treating potential. In the case of Euglenaphycin, a colleague of Peter’s working on a renal cancer decided to test it out. So far, the results are promising.

But the uses of this particular toxin may not be limited to potentially treating cancer. Peter explains:

”When we discerned the structure of Euglenaphycin – good chemistry, we go into the literature and find out if it’s known – and it was a new molecule in and of itself, but it’s related in structure to fire ant venoms, the solenopsins they’re called. And a lot of people have, and are still working on, a lot of bioactivity with the solenopsin, which include they’re antibacterial, they’re antiobiotics, they’re antifungals, and they actually work on oddly enough another really nasty marine organism called microcystis. Microcystis affects drinking water throughout the country, and in fact in Lake Michigan and some of these others, it can become a real big hazard. In the presence of euglena, microcystis growth is greatly retarded, and that shows some very specific activity that we would like to go in and harvest and maybe we can have a natural algacide that we can naturally go in and control or mediate another problem. And that’s the advantage of my job. I really love that part of my work. We can turn something from the dark side to the good if we can.”

While it’s fantastic news that this toxin may someday provide new tools to help humans, it’s important to remember that it is out there in the wild, where it may pose a threat to fish, animals, and humans. Peter said that the intense toxicity produced by the algae is something that we need to be very concerned about.

”One of the things that just happened recently about two weeks ago on the Euglenaphycin story is that historically, since 2004, we knew it was killing fish. As, I think it was two weeks ago in Michigan, a calf died (or maybe more than one, I’m not sure) died drinking water out of a pond, and the organism responsible that was just identified was Euglena. Now that’ll be the first case where a mammal was actually shown to die. What that means for me now is that we have to develop detection methodologies for drinking water reservoirs: lakes, ponds, rivers, things like this, to see to it that if that organism’s present we’re taking the right precautions. Now when we first started, we thought, well It’s killing fish. OK, we’ll monitor fish ponds. But now that it’s killing mammals, which isn’t a surprise, we use mammal assays all the way through, and it appears the toxicity in and of itself is now easier to detect … and some of the reports I have now in fact, including in the paper we published, it now affects close to two dozen states in the U.S. already, and my guess is it’s affecting a lot more.

Now at this point, you may be wondering how such a toxic chemical could have gone unnoticed or unreported for so long. Is Euglena producing toxins more often now, or could it be that this toxin has always been around, and we’re just unlocking this mystery now because we have better scientific tools. Peter said this is a hard question to answer, but that the answer may be somewhere in the middle.

”Our monitoring and detection tools have become so much more sophisticated and much more reliable, so one the one hand, yes, I think we’re looking for things better than we have done in the past and maybe that’s why we’re finding problems and identifying problems that have always existed, but now we can characterize them. But on the surface, it does appear that the activity of some of these microtoxins is increasing in incidence. And so whether these organisms are capable of developing toxin producing mechanisms over time could also be happening. We see that happening with a number of dinoflagelletes – these marine algae – seem to have that ability, to turn toxin production on and off depending on environmental stress. So it appears that way. I know I’m solidly on both lines of that fence, but we don’t really know, but it does appear that these toxics events are increasing in incidence.”

What is clear is that there is much more to learn about Euglenaphycin. Peter said that the main goal now is to test the toxic compound for a variety of uses. And at the same time, research will continue that will hopefully lead to ways to detect, monitor, and control the production of the toxin in nature.

”The next step is a couple of things. We did get a patent out on this ... and what that allows us to do now is we’re going to have to produce enough of this stuff to test, either through natural sources – actually mass culture euglena – which my colleague in USDA – that’s kind of what he’s doing right now. And when we have milligrams to grams of the toxin, we will submit this to the various people who would like to test it and potentially develop it for it’s uses, such as antibacterial, anticancer, or antifungal, etc. So we can actually get some commercial development out of this material for good. The research is pretty much done on our end, we’re just going to be crunching purification processes now, I won’t say that’s trivial, but the fun part of it, the difficult part of it, is over. Now my colleague has to learn what happens in nature to either enhance or turn off toxin production, that’s a real fascinating area, because if we can understand that, maybe we can mitigate, or remediate, or stop the production of toxin even in nature. That’s out of my immediate expertise, but it’s a fun area to watch these people work in.”

Closing

Many thanks to Peter Moeller from NOAA’s Center for Human Health Risk, part of the National Ocean Service’s National Centers for Coastal Ocean Sciences. Peter works at the Hollings Marine Laboratory in Charleston, South Carolina, and he’s one of the lead authors of a new study about this powerful fish-killing toxin that’s slated to appear in an upcoming issue of the journal Toxicon.

Let’s leave Peter with the last word:

”Nature has the compounds out there for us. And it’s amazing, if we just go out and look for them, based on activity, I think we’re going to see a whole new generation of much more selective, much milder pharmaceuticals and antibiotics than we’ve ever seen before, and it’s because there’s a new, a rejuvenation of discovery to go out there and find them.”

If you’re looking for more news and information about our oceans and coasts, head over to the NOS Web site at oceanservice.noaa.gov.

If you have questions about this week’s podcast, about the National Ocean Service, or about our ocean, don’t hesitate to send us an email at nos.info@noaa.gov. We’d like to hear from you. That’s all for this week.

Let’s bring in the ocean....

This is Making Waves from NOAA’s National Ocean Service. We’ll be back in a couple of weeks with a new episode.


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