Aug 16, 2016

Interview Transcript

Interviewer: Killing malaria with light? We'll talk about that next on The Scope.

Announcer: Examining the latest research, and telling you about the latest breakthroughs. The science and research show is on The Scope.

Interviewer: I'm talking with Dr. Paul Sigala, Assistant Professor of biochemistry and the University of Utah. So Dr. Sagala, malaria isn't something that we think of a lot in the U.S. but it's actually quite a problem in other parts of the world. Can you talk about that a little?

Dr. Sigala: Malaria is really one of the most urgent health problems facing the world. It has been for many decades. Even now with all of our great public health advances, hundreds of millions of people every year around the globe get infected by the malaria parasite, leading to nearly a million deaths. Tragically, most of those deaths are among children under the age of five in Africa.

Interviewer: There are treatments for malaria. How effective are those?

Dr. Sigala: We currently have good treatments. So artemisinin in combination therapy is the frontline therapy and has really been an amazing drug that's saved millions of lives so the importance of was recognized. The discoverer in China was awarded, or shared the Nobel Prize last year. But like most of the drugs that have come before it, eventually parasites come up with ways to develop resistance. And so much attention right now is trying to devise either new drugs that can be combined with artemisinin to overcome that resistance or other ways to combat or reverse multi-drug resistant.

Interviewer: Part of what you're trying to do is understand how malaria works so that you can come up with ways to block it. One of the ways you're doing that is looking at how it interacts with heme, which is part of our red blood cells.

Dr. Sigala: Right, so parasites infect red blood cells, which are the most heme rich cell in the human body. And parasites also utilize heme as a cofactor in its own heme proteins. So it needs a way of getting heme and so we've been looking at how the parasite is able to either make its own heme or scavenge our heme within the red blood cell.

Our red blood cells, during their early development stages, had their own heme biosynthesis enzymes that were massively productive in generating lots and lots of heme. And those stick around in the mature red blood cell. They're not ordinarily active. But what we found with the parasites living inside, that we came up with a way to hyperstimulate the activities these enzymes in a way that allows us to kill the parasite.

Interviewer: Help me understand this. So you can take advantage of some of the heme synthesis tools that happen to be floating around in our blood that we make.

Dr. Sigala: That's right. So these are enzymes that are inside the red blood cell but are no longer active because our red cell heme synthesis petered out at the end of development of those cells. But the enzymes are still there, so when the parasite is inside it now has the enhanced ability to take up nutrients and other compounds from the serum. And so one of the compounds that we found that we could put in actually stimulates the activity of these remnant human enzymes that are there. And some of the intermediates that accumulate as a consequence of that activity actually sensitize the parasite such that when we hit the parasite with light it kills it.

Interviewer: What is the light doing?

Dr. Sigala: So there are classes of compounds that are phototoxic. Meaning that when they absorb light they lead to generation of what are called reactive oxygen species, or really reactive molecules that kind of rapidly react with all sorts of biomolecules and just kill the cell in which they're generated. This is utilized for a form of cancer therapy, which is called photodynamic therapy and we think there are possibilities for adapting this approach for potentially treating malaria.

Interviewer: So how can you do that? I mean, first of all, how are you even getting light in there? This is inside your body.

Dr. Sigala: That's right. So that was part of the creative challenge here. It's not very practical to imagine inserting a fiber optic cable in someone's blood stream and trying to illuminate every infected cell. It's additionally challenging because falciparum malaria sticks to the walls of our blood vessels, so called sequesters, which means a lot of the really mature forms are not in active circulation which makes it difficult to target them.

So we wanted to devise a strategy that overcame the reliance on an external light source and what we figured out is that we could use a compound called luminal, that's a very well characterized chemi-luminescent compound. Meaning it's a small molecule that gives off light. And when we combined luminal with other compounds to simulate heme biosynthesis that those would converge within the parasite infected red blood cell and would generate light within that cell and selectively kill the parasite.

Interviewer: I think you had told me once before that the luminal is actually what's in glow sticks. Right?

Dr. Sigala: That's right. So it's commonly used in glow sticks and also in police departments for forensic reasons for trying to identify blood at blood scenes because one of the curiosities of luminal is that it needs to be activated. And it gets activated by interactions with iron so heme has iron in it. So blood that's a blood spot at a crime scene is exposed to the air and so when you spray luminal in it, it activates it.

But chemistry is also what contributes to the specificity of luminal targeting the malaria parasite. Because it requires this iron activation mechanism, most human cells tightly sequester iron and it's not readily available. But the parasite during its normal 48-hour cycle degrades up to 80% of all hemoglobin within a human red blood cell, breaks the protein part up into amino acids. The heme though, it basically sequesters into a vacuole so all of the iron within that heme is now much more exposed than it would be in a healthy red blood cell. Which then provides ready access to then activate luminal when it is delivered.

Interviewer: That's very convenient.

Dr. Sigala: It is.

Interviewer: So how are you investigating this in the lab? Kind of what stages are you at?

Dr. Sigala: Right, so what we have so far have done is explored in principle whether in an x-vivo culture system can actually potently kill the parasite with this type of combinatorial treatment. And the answer is yes, we certainly can. What we discovered along the way is that not only is the ALA, amino linoleic acid, plus luminal effective, but it synergizes very well with the current antimalarial compound, artemisinin in what is really a new twist. And so the combination of all three of those compounds is extremely potent in vitro at killing the malaria parasite.

So the next challenge is really to ask whether this will be effective in vivo. That's challenging to do directly in humans but one can turn to studies with plasmodium species that infect rodents. There are mouse malaria and those provide a ready means to ask, can we cure a mouse from malaria using a combinatorial treatment with these compounds?

Interviewer: Something else I wanted to bring up is that the parasite that produces malaria is actually somewhat mysterious. There's actually a lot we don't know about it.

Dr. Sigala: That's right. For a bug that we've been battling for thousands of years and especially in the current age of understanding so much about genes and genomes, it's unusual. It's an opportunity to deepen our understanding about how a highly effective parasite carries out its mission and devises clever new strategies to survive within our cells. So it teaches us something about general mechanisms in biology, but more importantly it means there are opportunities because those genes and potentially the proteins themselves are so different from our own proteins that we can selectively target them if we're able to understand their functions in a way that really avoids toxicity to our bodies.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.


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