WKCR: The Malaria Mystery

Malawi_GlobalHealth_Project_2013_09-99

The Malaria Mystery was the third of a four-part, summer-long series of multiple-part episodes of The Best Medicine on WKCR-FM.

We could completely eradicate malaria worldwide, say experts like Drs. Johanna Daily and Myles Akabas of the Albert Einstein College of Medicine. If so, why haven’t we? Malaria kills about half a million children die each year; that’s the equivalent of five to seven jumbo jets of children crashing per day. What might new treatments look like? How do we improve health care in malaria-infested regions? And what will it take to move business and political leaders to fund the final eradication of the disease? In this three-part series, we try to unpuzzle the science and logistics of ending malaria.

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Erik Campano: I’m Erik Campano. Today: The Malaria Mystery, Part I.

Scientists say it’s completely possible to eradicate malaria. So why haven’t we done it?

Myles Akabas: There are probably three to four billion people in the world who live in malaria-endemic regions. About 200 to 250 million of them contract malaria each year, and about 600 thousand die, mostly in sub-Saharan Africa, and mostly children under the age of five, and pregnant women. So there’s a huge morbidity and mortality due to malaria.

Drs. Myles Akabas and Johanna Daily, of the Albert Einstein College of Medicine in New York City, will help us unpuzzle the biology, economics, and logistics of ending malaria. This is The Best Medicine. Stay with us.

Part I

Campano: I’m Erik Campano. On this program, we’ll speak with Drs. Johanna Daily and Myles Akabas at the Albert Einstein College of Medicine of Yeshiva University in New York City. Johanna has treated malaria around sub-Saharan Africa, and along with Myles, is a researcher looking into the physiology — and new treatments — for this disease, which kills hundreds of thousands of people a year.

From WKCR 89.9 FM and WKCR HD-1 Columbia University, this is The Best Medicine: Healthcare and humanity, one story at a time, a radio show and podcast that uses storytelling to shed light on medical conditions through a new prism: not only as biological science, but as a shared human experience, a source of compassion, and a well of hope. Now: The Malaria Mystery, Part I.

The extent of destruction of malaria is hard for the human mind to comprehend. About half a million people — mostly children and pregnant women — die every year from malaria. As Myles points out in part III of this program, that’s the equivalent of five to seven jumbo jets full of children crashing every day. Every one of those children, or victims, has a family and a community that suffers along with them. So millions upon of millions of people experience terrible pain as a direct result of malaria — and yet experts, like Myles and Johanna, say that from a scientific point of view, this may all be completely preventable.

Myles and Johanna were generous enough to give us their time to discuss what malaria is, and what can be done about it. In this, Part I of III, we’ll begin with an overall look at the illness, and at Myles’ research into a way of screening for potential compounds which might be used as anti-malarial drugs — and which might prevent the disease from spreading.

We talk a lot about other infectious diseases in the United States. One that comes to mind recently, of course, is Ebola. And malaria, while it causes hundreds of thousands of deaths around the world each year, does not get a whole lot of press. And so we need a primer.

What is it? Where does it occur? What do the symptoms look like? Why does it cause so much death? And what’s it like on the ground?

Maybe, Johanna, you want to tackle the basics.

Johanna Daily: Thanks Erik. Well, thanks for inviting us to talk about one of our favorite subjects, malaria, and I think a key to understanding malaria has to do with understanding the lifecycle. The reason it’s important to understand it, is you can then start to think about where we can intervene to prevent transmission. So, the plasmodium is a species, there are multiple plasmodia that can infect humans. There are five but there are many many more that infect other parts of nature.

Campano: Plasmodium is a parasite.

Daily: And plasmodium is a parasite, a protozoan parasite, and it has this intricate life cycle. And, I’ll start with that, and I’ll start with an infected human.

So, there’s probably millions of folks around the world that are infected with malaria, but they are in restricted areas, and they are in restricted areas that support the vector, the anopheles mosquito, which takes a blood meal. The female anopheles takes the blood meal. She needs it for nutrition, and when she takes her blood meal she accidently ingests some of these malaria parasites. And, over about two weeks, after she ingests them, they become now an infectious parasite. And so, when she takes her second blood meal to some other unsuspecting person, she now infects them.

And this now starts the human phase. So within minutes, she injects these things called sporozoites. They find their way through your soft tissue and skin. They go into small blood vessels and they get carried to the liver.

And, that is an absolute key step. People don’t really understand this part of the biology, and it’s a key part. Because there’s only a few parasites. So, if we could stop the life cycle there, there’s going to be a big victory. There’s very few parasites. Once they make it to the liver, they invade a liver cell, and then they multiply over two weeks, to millions to billions of parasites.

During that stage, you’re completely asymptomatic. You’re an unsuspecting reservoir. You’re having this huge expansion of infection in the liver. You have no clinical symptoms. We don’t have any blood tests to say who’s got the liver stage — which is again a difficult thing, if you want to eradicate — and then all of a sudden one day, they burst out into the blood stream, and then they infect red cells. And, as it invades the red cell very quickly, it goes through life cycle stages, either two or three days duration, bursts out, and now increases logarithmically your infection.

So over time, you generate this huge burden of foreign proteins and products that our immune system responds to, resulting in fever, chills, and in some cases, if you have no immunity, death.

Now, within these parasites that are happily growing in your red cells, a small percent become sexual forms — most of them are asexual causing disease, a small percent become sexual forms — and when the mosquito picks up a blood meal, she takes on not only the asexuals, but the sexuals — and that’s the stage that now results in development of the next infectious stage.

So that’s the other key choke point. If we could figure out why some become the transmissible form, that would also stop eradication. So, really, in summary, it’s: if we can control the anopheles vector, if we can control these different stages throughout the body, the skin, the liver, the bloodstream stage, the transmissible form, we could then probably decrease the reservoir which is us humans, and then prevent transmission.

Campano: Is this only human-to-mosquito-to-human transmission? Or can mosquitos get it from members of other species?

Daily: That is a great question, because you’re getting to the question of whether we can eradicate malaria. And the good news is, there are really only human reservoirs. There’s the rare case, that maybe someone gets a simian malaria —

Campano: — simian meaning —

Daily: — from a macaque or a monkey. But that’s rare, and that’s why malaria is eradicable, unlike other parasites that infect animals in the forest. Those we can never eradicate. You couldn’t chase down all of the animals. So that’s why malaria is possibly something we can eradicate.

And, I will remind you that one of the species of malaria used to be endemic to the United States. And, this was a big issue particularly when we were training our troops down South.

So, our troops would get sick. They would get fevers. They weren’t able to perform, so it was actually the US Army Corps of Engineers that helped eradicate malaria. And, they focused on the mosquitos. If you don’t have mosquitos, you don’t have transmission, so they spent a lot of time draining swamps, killing mosquitos, and so they eradicated the South. They eradicated — I think parts of D.C. had malaria, I think actually most of the United States —

Akabas: Malaria was endemic in the south of the United States, and up to Washington from colonial days. And, in the early colonies, you hear of writings of people leaving Washington all summer to avoid malaria. Certainly in the South, the rich people would migrate up to the highlands, to get out of the lowlands, in the summer, to avoid malaria, in colonial times.

Campano: Why is it important that we eradicate malaria?

Akabas: Well there are probably three to four billion people in the world who live in malaria-endemic regions. About 200 to 250 million of them contract malaria each year and about 600,000 die, mostly in sub-Saharan Africa, and mostly children under the age of five and pregnant women. So, there’s a huge morbidity and mortality due to malaria, but it’s mostly out of sight of Americans.

Campano: How was it eradicated in the US and in Western Europe?

Akabas: Largely through the spraying of DDT to eradicate the mosquitos, and the drying up of the swaps to eradicate the nesting places of the mosquitos. And, malaria was successfully eradicated in the United States in the period around World War II, and then also in the Mediterranean basin, malaria was described in the ancient Roman medical literature, and was endemic around the Middle East, the Mediterranean basin, and after World War II was completely eradicated there, too.

Daily: Exactly, and so the key thing is the vector and what happens is we can’t kill mosquitos forever, but what happens is the population or reservoirs eventually, either you treat them all or malaria comes out of their body. So, eventually mosquitos come back, but then there are no remaining reservoirs to continue transmission.

So there was this profoundly successful campaign to eradicate malaria, as you were saying, and in India as well, they brought it down huge levels. But then they became, in the 70s, discouraged. They realized they couldn’t make serious inroads in decreasing transmission in Africa, so they sort of gave up. India sort of backed off their control practices, and then malaria came back up.

Campano: So what precisely is the difficulty in finally eradicating it in places like sub-Saharan Africa? Is it that you have to get to pockets of mosquitos that are hard to get to? Or communities?

Daily: Well I think there’s a couple of things there. One, are areas where the transmissions are already low, so it’s getting those last few cases. So that’s a completely different challenge then areas that ecologically have such a tremendous burden of mosquitos. They have swamp lands and they have incredibly high transmission. So, there would be a different sort of attack strategy for an area where there’s just a profound amount of infection. and then everyone perhaps in the neighborhood or village is infected.

But I agree with Myles, that your best bang for your buck is going after the mosquito.

The other thing we do is bed nets, it’s hard to use a bed net every night. Imagine being in a very tropical area, having to climb under a bed net, it feels even hotter. Imagine if there is a little hole, or you get holes from a tear. So, I think families do the best they can by putting their high risk children under the net, but adults often don’t sleep under their nets, but they are the reservoir so it’s sort of a catch-22.

One alternative solution that we don’t hear a lot about is actually building houses that have screens. And, that’s what the rest of the world has done to prevent mosquito bites.

Akabas: Abject poverty is a significant problem for treatment of malaria. The people who are getting malaria are very poor. They can’t afford to pay for treatment in many cases. They can’t afford to buy screens for their houses when they can barely afford to feed themselves. They’re so poor they don’t have access to good medical care. For many of these people, they live several days from the nearest health facility, and they just tough it out, when they have malaria. And so, they remain a continual reservoir that provides infected mosquitos.

Campano: It would be really helpful if you could paint a picture of, when you enter into a community — say in sub-Saharan Africa — you go to a clinic. You walk in there. The people, what are they experiencing? How does it affect their families? How does it affect their community? What’s it like to be on the ground treating malaria?

Daily: Right. I’ve worked in clinics in Rwanda, Senegal and Malawi, and basically you go to the local health clinic, and people usually come very early in the morning. So they come, in some cases, from very far away as Myles said, and they line up, and they usually have symptoms of malaria, fever, chills, not feeling well, and it’s usually their children who are ill, and they’re lining up waiting patiently, and quietly, for their blood smear. And, if they’re positive, either they’re given anti-malarials if it’s part of some sort of control program, or they’re given a prescription.

And, by one or two o’clock in the afternoon basically everyone’s had their smear and then you start this over the next day. Then for children often who have severe disease, they’re sort of brought in any time of day or night. They come in with coma, and they’re treated in a local hospital if there’s one close by. And often there are stock outages.

Campano: Stock outages. OK.

Daily: So there are no anti-malarials. I just got off the phone from one of the sites I work in, and they are running out of anti-malarials. And, this happens all of the time. So, the villagers have no choices, but this is sort of what they’re faced with: a lot of challenges.

Campano: I’m Erik Campano, and this is The Best Medicine from WKCR, Columbia University. On this program: The Malaria Mystery, Part I. We’re speaking with Drs. Johanna Daily and Myles Akabas, researchers at Albert Einstein College of Medicine in New York City. Myles is part of a lab which is looking into new treatments for malaria. Or, to be specific, he and his fellow scientists have found a new technique for screening drugs for the ability to kill P. falciparum – that’s the parasite that causes the most deadly strain of malaria.

One of the compounds in the human body that the parasite requires in order to live are purines, and your research is about how to prevent the purine from getting to the parasite, who then can’t survive. I think I way oversimplified it right there, but maybe you could begin the process of laying out exactly what’s going on.

Akabas: So purines are a critical component of DNA. If you think of DNA as the nice double helix where you have the two strands and the steps going up, those steps consist of two different chemicals. One is a purine, and one is a pyrimidine. The parasites can make the pyrimidines, but they can’t make the purines, and so they have no source of purines unless they import them from the host red blood cell, or from the liver cell —

Campano: — and without DNA the organism cannot —

Akabas: — the organisms can’t replicate themselves and they die. So, the parasite once it invades the red blood cell, or when it invades the liver cell in the earlier stage of the disease, needs purines to be imported from the host cell, so that they can replicate their DNA and make the daughter cells. So, they need to import purines from the host cells, and they do that with a protein called an equilibrative nucleoside transporter. This is a protein that is imbedded in the cell membrane of the parasite. And, what it does is pick up purines from the cytoplasm of the host cell, and import them into the cytoplasm of the parasite.

Campano: So they’re like thieves? — kind of —

Akabas: Yes! They’re parasitic. They’re utilising the nutrients of the host for their own use. And, we came up with a way of actually identifying compounds that would inhibit this transporter, so that we could get potential starting points for the development of novel anti-malarial drugs.

Campano: In other words, you’ve found chemicals that are able to target this transport protein?

Akabas: Yes.

Campano: You were able to isolate the gene — the DNA — that codes for the transporter. In other words, the DNA that when it’s —

Akabas: — translated into protein —

Campano: — is translated into proteins creates this transporter. You were able to take that DNA and put it in a yeast cell, and then the yeast ended making these transporter proteins.

Akabas: They make the malaria transporter. And, we then had a very simple assay.

Campano: An assay is a test.

Akabas: An assay is a test. Malaria purine transporter would transport a compound that was toxic to the yeast. So, we put that compound into the media that the yeast were growing in. It enters the yeast through the malaria purine transport protein, and kills the yeast. And now we add different chemicals, and we see: do the yeast grow?

The only way the yeast can grow is if one of those chemicals blocks the transporter, and prevents this toxic compound from being transported into the yeast.

Campano: OK.

Akabas: And so one does these assays, these tests, in plates that have 96 wells or 384 wells — or the pharmaceutical industry has plates that have 1536 wells — and they’re very, very tiny when you get 1536 wells. It’s less than a drop of fluid. But, we could put a small number of yeast into a well, with the toxic chemical, and with a library of other chemicals, and then let them grow overnight, and the next morning we could look at the plate, and see where the yeast cells had grown, and we’d then know that the chemical that went into that well, in the plate, was inhibiting the malaria purine transporter, and allowing the yeast to grow.

We screened a library with our collaborators at Columbia University and Don Landry’s lab — a 65 thousand compound library. We found 171 hits and then in subsequent work characterized the nine best hits.

Campano: Wow. So in other words, you looked at 65 thousand different chemicals that could possibly inhibit this transporter and 171 of them actually did it. And then, among those 171 —

Akabas: We picked the best nine simply because we had very limited financial resources and a sample of each one was 50 to 100 dollars. And, the manpower to do all of the follow-on testing, to prove that this really worked, was very costly, so we limited ourselves to nine of the 171 compounds.

Campano: And these compounds that inhibit these proteins, what are they? Do they have anything in common?

Akabas: Do they have anything in common? Four of them looked structurally similar, but there were five different structural classes of compounds, out of the nine compounds, and eight of the nine have one feature in common, and that is they have two fused-ring structures, which sort of look like a purine… if you’re not a chemist.

Campano: So, in other words, because they’re similar to purines, do you think that that causes them to be able to attach to the structure, in the same way that purines do?

Akabas: So that would be a hypothesis. [laughter] We would love to be able to develop an x-ray crystal structure of the transporter with these compounds bound.

Campano: In other words look at it very, very, very, very, tiny and closely —

Akabas: — looking at it at an atomic level structure. That turns out to be very, very difficult for membrane proteins.

Campano: Right.

Akabas: So if we had more resources, we could go after that, but right now we don’t have the resources to try that line of investigation.

Campano: Does that matter much?

Akabas: Having a high resolution structure of the transporter, with one of these compounds bound, would be a huge advantage. Because then you can see how it fits into the binding site, and how you can then manipulate the chemical to make it interact with other parts of the protein in that region, and bind with higher affinity.

Because it’s not just how potent it is. It’s also got to be absorbed from your intestine. It’s got to be stable. So, if you want a compound that’s going to treat malaria, it’s got to be stable at 100 degrees temperature, and a hundred degrees humidity.

Campano: And, it has to not have too many side effects, it can’t kill the patient in some other way.

Akabas: Absolutely, so it can’t be toxic to the patient, and a lot of the people who are being treated are young children and pregnant women, where the liabilities and the degree of acceptable toxicity is very limited.

Also, to avoid resistance developing in the parasite to the compound, you hopefully want it to be a compound that could work with one dose. So, you hand the patient a single dose. They take it. It irradicates the malaria from them, and then you don’t have problems with patient compliance — that they feel better on day two, and they stop taking the medicines.

Campano: OK. So in terms of the compounds – these eight or nine compounds that you’re working with – how many steps forward toward the actual drug are you?

Akabas: You never know the answer until you get there. So at this point we got a grant from the National Institutes of Health, that was funded in February, and our collaborators at Columbia and Don Landry’s lab have started synthesizing derivatives of some of the nine compounds, to try and make new compounds that we have been testing, to try and see if we can prove the potency of the compounds, and the first round of compounds that they made — one of the derivatives was about fivefold more potent. So it’s in the right direction.

We have a long way to go.

Campano: Dr. Myles Akabas, speaking with Dr. Johanna Daily, about research into ways of finding new drugs to treat malaria.

When we look at the death toll from malaria — about half-a-million people worldwide each year — and hear Myles explain that with just a bit more funding, research into treatments could make leaps and bounds, it raises interesting questions about what value we, as humanity, put on a single life.

According to the World Health Organization, about one or two billion dollars is spent annually, globally, on malaria control. One might be tempted to make a comparison to, say, military spending, which the Department of Defense reported this year to be just under 500 billion dollars, or to entertainment, on which Americans this year spent about 200 billion dollars.

But — and the question is not disingeuous — what use this comparison? When looking into the eyes of a child suffering from malaria, does one have the energy to think about the extra resources that could have been put into its control, a long time prior? These are the kind of issues that we’ll explore on parts II and III of The Malaria Mystery.

The conversation continues at thebestmedicineradio.com. You can read a transcript, leave your comments, and learn more about the guests and resources mentioned on this program.

The Producer of the Best Medicine is Linh Tang, the Marketing and Technical Director is Jean Kremer, the Content Editor Evan McWilliams, the theme music composer Tim Hoyt, and the graphic designer Gabe DeSanti. I’m Erik Campano.This program was originally broadcast on June 29, 2015. The Best Medicine is a production of WKCR 89.9 FM and WKCR HD-1, Columbia University in the City of New York.

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Campano: I’m Erik Campano. In this episode: The Malaria Mystery, Part II. Scientists say it’s completely possible to eradicate malaria worldwide. So, how are we doing?

Daily: There are many, many more countries that are being added to the pre-eradication, and eradication, list. So there’s no question that there’s been huge improvements over the last ten years. And, we just have to continue moving those forward. So I think the good news is, actually, that there’s been a lot of progress.

Campano: Drs. Johanna Daily and Myles Akabas, of Albert Einstein College of Medicine in New York City, will delve deeply into the science and logistics of ending malaria. They’ll discuss possible new anti-malarial drugs, and what kind of resources are needed to keep this infection contained. This is The Best Medicine. Stay with us.

Part II

Campano: I’m Erik Campano. On this program, we’ll speak with Drs. Johanna Daily and Myles Akabas at the Albert Einstein College of Medicine of Yeshiva University in New York City. Johanna has treated malaria around sub-Saharan Africa, and along with Myles, is a researcher looking into the physiology — and new treatments — for this disease, which kills hundreds of thousands of people a year.

From WKCR 89.9 FM and WKCR HD-1 Columbia University, this is The Best Medicine: Healthcare and humanity, one story at a time, a radio show and podcast that uses  storytelling to shed light on medical conditions through a new prism: not only as biological science, but as a shared human experience, a source of compassion, and a well of hope. Now: The Malaria Mystery, Part II.

In the first part our program, taped at Albert Einstein College of Medicine, Myles, Johanna, I, and our Technical Director, Jean Kremer, looked at the amount of suffering that malaria causes worldwide. About half a million children and pregnant women die every year from malaria. We discussed the history of how it was eradicated in the US and western Europe. This involved draining swamps and spraying DDT to kill off mosquito populations. Doing the same, now, for the entire world — and in particular, the malarial regions of sub-Saharan Africa — would require a massive effort costing billions of dollars. As part of that effort, Myles is working on techniques for finding drugs that target malaria. They stop the work of proteins necessary for malaria to spread in the body, by preventing a molecule known as a purine from being transported into the malaria parasite.

Campano: Let’s take these “anti-purine transporter compound possible drugs”… is that a good label for it?

Akabas: Sure.

Campano: What do you call them?

Akabas: Therapeutic leads. They’re potential lead compounds, that you could start developing, towards a potential medicine.

Campano: Let’s put those in the context of malaria treatment. Maybe you could lay out: what are the ways we treat malaria now, and how this would fit in? Also, what’s interesting is how different this type of tact toward the disease is, compared to our current treatments.

Daily: Right, so there aren’t that many anti-malarials actually in existence. There’s probably five or six. And if you have a drug-sensitive parasite, they’re very effective. So the keystone drug is artemisinin, and we always partner it with a second drug, because the parasite will become resistant to a single agent. And, so that has worked well, and drug resistance has not been an issue, but as Myles said: in southeast Asia, we started hearing reports of drug failures. That is sort of devastating, because they’re resistant to the artemisinin, which is the cornerstone drug, and there aren’t a lot of drugs in the pipeline.

Campano: Artemisinin — does that only target one of the species of parasite? Or all of them? Or some of them?

Daily: So, there are five species of human malaria. Falciparum is the one that causes the most mortality, and that is the one that is drug resistant.

The other human malarias are still sensitive to chloroquine. So, for what we call the benign malarias, we use chloroquine. So, vivax, which is probably the most prevalent malaria in the world, gives you fever, chills, rarely kills you — still chloroquine sensitive.

Campano: That’s the most prevalent.

Daily: That’s the most prevalent.

Campano: What are the numbers on that?

Daily: Well, I think altogether, all the malaria species — there are millions of cases worldwide.

Akabas: Hundreds of millions. About 200 million cases worldwide.

Daily: 200 million — that includes all types of human malaria. There are five species. Number one is vivax — but doesn’t kill you — number two is falciparum. The problem with falciparum is: it’s fatal in non-immunes, and there’s drug-resistance. So, it’s sort of a double whammy on the most important species. There is a fifth species calledknowlesi, which just recently came over from the macaques. That can kill you also. It’s very rare, probably chloroquine-sensitive.

Campano: Is there a danger, that that could spread?

Daily: Probably knowlesi not, because it really needs to be next to its animal reservoir. So, human-to-human transmission hasn’t been reported. So, it’s going to keep the area restricted. You have to be living near an infected macaque —

Campano: A macaque.

Daily: — that’s infected. So unless it makes an evolutionary change, that it can be efficient from human to human, that we’re probably OK with. So, drug resistance, unfortunately, is linked to the fatal malariafalciparum.

And so right now, if you don’t live in one of these regions where artemisinin has been reported — as high as 67% — you’re going to be OK. Right now in Africa, where most of the falciparum is, we don’t see any of the molecular markers of artemisinin resistance. The good news is we know where the mutation is, in the parasite. So, we can easily screen. And, clinically, we haven’t seen it, but we are absolutely concerned that it will make its way to Africa, and the problem is that there are not a lot of alternative drugs in the pipeline.

That’s why the work that Myles and other people are doing to find completely brand-new targets is becoming more important.

Campano: OK. Just to summarize this: two hundred million people, approximately, in the world, out of our population of seven billion, approximately, or eight billion, get malaria in a year. And among those 200 million —

Akabas: — about a quarter to a third of the cases are falciparummalaria.

CampanoFalciparum.

Akabas: About 40 to 50% are vivax malaria. And then, ovale, malariaand knowlesi are very rare.

Daily: They’re very small.

Akabas: 80% of malaria cases are vivax or falciparum.

Campano: OK. And the falciparum cases have a mortality rate that’s significant.

Akabas: In children and pregnant women.

Daily: And non-immunes. So, if any of us, who do not have immunity, because we were not born and raised in an area where we were exposed, we would have mortality. So, everyone’s at risk for death withfalciparum, unless you have clinical immunity, which is not well-understood. And you develop it if you survive, and live, in a region where you’re getting constant exposure to the parasite, such that older adults in the village may have zero symptoms, but they’re carriers. But any of us, who have not been exposed, would succumb to falciparum. That’s why when travelers go to falciparum-endemic areas, we give them preventative medications.

Akabas: You can be repeatedly infected by malaria. So, you don’t get immunity in the same way as you get with chicken pox and other viral illnesses. You basically get chicken pox once in your life, and you never get it again. With malaria, you can have it multiple times, but you develop a degree of immunity that prevents you from having severe malaria. So, it allows you to contain the infection, so that your symptoms are less severe. And, if you leave a malaria-endemic region, and live elsewhere for many years, and then go back, you’ve lost that degree of immunity in many cases, and you can now have very severe malaria.

Campano: And, why this is the case, is actually not very well understood.

Akabas: Well, part of it is that the parasite spends very little time outside of a human cell, and so there’s not a lot of time for the immune system to see the parasite, recognize it as being foreign, and mount an immune response to the parasite that would be fatal to the parasite.

So, there are certain points where there are very few parasites, such as when the mosquito bites,a and introduces the infectious form, the sporozoite form, there are as many as a hundred sporozoites to a thousand sporozoites introduced with that bite.

So, if the immune system could recognize those sporozoites, and either, through antibodies or immune cells, recognize and destroy those sporozoites, they’d never get to the liver — but there’s only 30 minutes between the mosquito bite and when they get inside a liver cell. And once they get inside a liver cell, they’re basically safe. And then, once they rupture out of the liver cell, as twenty or thirty-thousand infectious daughter cells, they’re in the circulation, free in suspension, for maybe 30 seconds, before they internalize themselves into a red blood cell. So the immune system has very little time to, sort of, interact with the parasite.

Campano: It’s not possible, therapeutically, to target that 30 minute window, is it?

Akabas: Well, that’s been an attempt with vaccines, and certainly they’re trying to identify proteins that are expressed by the parasite, at that stage, that would be candidates for use in the vaccine, and there’s a recent trial that suggests that may be feasible.

Campano: Interesting. So in other words, in the 30 minutes between when the mosquito bites the person, and the parasite travels to the liver, that parasite may produce some kind of protein, and if we could —

Akabas: — it has proteins on its surface, and antibodies or immune cells could recognize —

Campano: — and attack it, before it gets to the liver —

Akabas: — right. The antigens are the proteins and the sugars that the protein expresses, that are different than the proteins that are made by the human host. And, if the immune system can be trained to recognize the parasite as foreign at that point, then you could mount an immune response that might be protective.

Campano: So that’s one possible avenue toward malaria treatment. What else is on the horizon?

Akabas: So, developing new drugs is clearly an important avenue for treating people who are infected. And as Johanna explained, the development of artemisinin resistance in southeast Asia means that eventually the artemisinins are going to be less useful.

So, there’s a group that has been supported by the Gates foundation, and a number of foreign governments, the Medicines for Malaria venture, and they serve as sort of a pseudo-pharmaceutical company that’s willing to spend money to develop anti-malarial drugs. So they act as a clearing house. If you have a compound that has good anti-malarial activity, they will help you get it through animal toxicity experiments, and if it passes animal toxicity experiments, they will contract out with some company to do first-in-human safety trials, in a phase one trial. And then, if it passes that — and they have a number of compounds in the pipeline — some are in phase 3 trials where they’re being tested in humans. And so, there are compounds in the pipeline that may make it to market.

Campano: Is there anything else?

Daily: So, just to remind you, in terms of thinking about other therapeutic options, if we go back to the life cycle stage, we can find other areas besides the sporozoites-in-the-liver stage. The parasite bursts out of the liver and infects red cells, and that’s another stage where we can make an antibody to the parasites, at that stage. The parasite lives inside the red cell, but it deposits parasite proteins to the surface of the red cell, which seems very odd. You would say, it should be sitting in the red cell, as a Trojan horse. But, it’s not doing that. It’s secreting proteins to the surface of the red cell, and those could be targets of an antibody. So that’s another place we could think about making a vaccine.

And then, if we could also target these sexual-stage transmissible forms — what if we had a vaccine that removed the transmissible forms? So that would be sexual-stage vaccines. And then finally, people have made antibodies that are taken up by the mosquito, and inactivate the mosquito stage. So, those would be transmission-blocking vaccines.

So in other words, if we are thinking about a vaccine, we could really target any of these life-cycle stages: sporozoite stage, liver stage, red cell stage, transmissible form, or vector stage. And people are working on all aspects, in terms of a vaccine.

Or, you could also use drugs, to target those different biological processes.

Campano: All of those sound interesting. Particularly interesting is the idea of actually getting at the malaria in the mosquito. That would be different than getting at it in the human, because in the mosquito, it’s not really attacking any of the internal organs, or anything like that.

Daily: So right, it’s killing the parasite within the vector. And people have looked at, again, these antibodies. They inoculate me with the vaccine, the mosquito takes up that antibody, and that somehow inactivates the parasite.

That hasn’t been successful, but that strategy has worked for Lyme disease. The vaccine actually kills the Lyme in the tick vector. That vaccine is no longer available, but it showed very good therapeutic efficacy.

Campano: How do you get the tick — or the mosquito — to get the vaccine?

Daily: OK — because they’re taking a blood meal, from me, and that’s actually the time that maybe the transmission will occur, and at that moment, it then will act on whatever’s going on in the mosquito stage, whatever the protein that’s being expressed in the mosquito, the vaccine is made to that target, and it inactivates it. And so that’s, again, called a sort of transmission-blocking vaccine, because it’s targeting what’s going on in the vector.

So that would be one — and again, people have looked at that. And another thing that sometimes is going on in the mosquito, believe it or not, mosquitos are infected with other bacteria, or other things — I think there’s a particular bacteria, that seems to interfere with parasite development.

So there have been some studies to manipulate the microflora of mosquitos, to see if that actually impacts parasite development.

Campano: Interesting.

Daily: And the final thing is, people try to engineer mosquitos, so they are not receptive to parasite infection. And, that’s been interesting, but that may be hard to completely replace nature’s mosquitos. But there’s been a huge effort, to genetically engineer mosquitos, have them take residence up in the wild, and then they’ll be resistant to malaria infection. So, that’s been another approach, in terms of trying to eradicate transmission.

Campano: You actually laughed about that, Myles.

Akabas: Yeah. The idea that we can genetically engineer mosquitos — because in most cases when you genetically engineer organisms, they may do very well in the lab — we have lots of genetically engineered mice — but when you ask that mouse to live in the wild, they don’t do very well. So, genetically engineered mosquitos may not be competitive with wild-type mosquitos. And so, the idea that you can actually replace the populations is probably pie-in-the-sky.

Daily: But you know, it’s a potential approach.

Campano: I’m Erik Campano, and this is The Best Medicine from WKCR, Columbia University. On this program: The Malaria Mystery, Part II. We’re speaking with Drs. Johanna Daily and Myles Akabas, researchers at Albert Einstein College of Medicine in New York City.

They’ve just shared with us some of the scientific approaches toward combatting the malaria parasite — work that invariably is part of any project to eradicate malaria worldwide. That would be a very valuable thing to accomplish, because the disease kills about half-a-million children and pregnant women every year.

What this speaks to is the amount of energy, effort, that people are putting into trying to deal with malaria, because it is such a serious problem.

Akabas: There’s no question. And, it’s not clear what the best approach is. And in many ways, pursuing very divergent paths is very important, because hopefully, one of them will work.

Campano: Is all the research — and clinical work in endemic regions — coordinated?

Daily: I would say, Erik, it is coordinated, in the sense that all of us have to present our work, either orally, or we publish it. And that’s how we know what each other is doing, and that’s how we share our results, and attempt to learn perhaps from what Myles is doing, somebody will be inspired from something he’s published, and then take it another direction. So in that sense, scientists are coordinated.

But in terms of some sort of institution puppeteering us, or controlling us, or having us work in a certain way, that doesn’t exist. And that’s probably good. Because people really need to go down their own creative paths, and passion, because what we do takes a lot of energy. And if that was controlled in some way, you may be less passionate about it.

Akabas: Yeah, centrally planned economies didn’t work in the Soviet Union, and centrally planned science probably doesn’t work, because no one individual, and not even a committee, can figure out what’s the best approach. And you have to explore lots of avenues to find out: we don’t know that our approach will work in the end.

It takes 10 years to develop a drug, so we’re right at the beginning, and it may not work. But, if we don’t explore this option, we’ll never know.

And that’s true for lots of different approaches to trying to treat and eradicate malaria. We don’t really know what exactly is going to work. And so, finding people who have a passion to pursue different avenues, and come up with creative approaches — I spent most of my career studying something else, and was drawn to malaria through a series of collaborations. And that has given me the opportunity to bring a lot of expertise, from completely different fields, to bear on malaria. And hopefully other people will be inspired to bring their expertise and their creative solutions.

Campano: So the major organization — or one of the major organizations — that’s funding campaigns against malaria is Gates.

Daily: That’s right. And Gates is really interested in control and eradication. They do some discovery work, but really it’s the National Institutes of Health that supports —

Campano: — “discovery work” meaning? —

Daily: — new solutions. Bill Gates is really interested in getting the RDTs out, making sure we have anti-malarials, making sure we have good clinical protocols, and he does a lot of other things. They do fund some very high-risk, out-of-the-box initiatives.

But most of the researchers are funded by your tax dollar at the National Institutes of Health, where we propose a scientific program to, in our cases, address malaria in very specific ways.

Campano: What about internationally, outside the United States? Who’s funding the research?

Akabas: Fundamental research, at the level of early-stage drug development is being funded in England by their Wellcome Trust, in Australia by the Australian equivalent of the NIH, in Europe by the European Science Agencies — there’s not a tremendous amount of funding for fundamental research in malaria. The Medicines for Malaria venture is funding the vaccine work, at more advanced stages, and drug development at more advanced stages. And then the World Health Organization does a tremendous amount to try and coordinate efforts to treat malaria in endemic regions.

Campano: So what are the numbers like, approximately? How much money each year goes toward malaria, both research and treatment?

Daily: I don’t know how to weigh all of this out, compared to other diseases like cancer or HIV. It’s a big number, but then you, on the other hand, were saying hundreds of millions of people have this infection, and what’s amazing about this infection is it is completely preventable, and completely treatable. And that’s the other thing that should be in the conversation.

Campano: It’s completely preventable, and completely treatable.

Daily: That’s right.

Campano: Yeah. It was eradicated here.

Daily: It was eradicated here, and so, if we have things already in hand — we know a lot about the mosquito — the other part that we haven’t really touched on is strengthening health capacity. So, to be honest, if we had enough health care workers, we had a full pharmacy, we had diagnostics, that should have a huge impact, as well, on these numbers of morbidity and mortality.

Campano: How much would it cost, in terms of dollars, to eradicate malaria, or almost completely eradicate malaria around the globe?

Akabas: Probably billions and billions of dollars. To build up the public health infrastructure in sub-Saharan Africa, to the point where you could treat the infected people, and at the same time, eradicate the mosquito vector so that you get a generation of mosquitos that wouldn’t have hosts to bite, is probably billions of dollars.

Daily: It’s maybe more than just money. It’s also infrastructure, training people, and simple things like dealing with stock outages. So it’s pretty complicated. I think the Gates have a very good strategy. It’s something to look to, in terms of how they’re attacking it. And they’ve also made tremendous progress. And there are many, many more countries that are being added to the pre-eradication, and  eradication, list. So there’s no question that there’s been huge improvements over the last ten years. And, we just have to continue moving those forward. So I think the good news is, actually, that there’s been a lot of progress.

Jean Kremer: And do you think that eradicating malaria would resolve a lot of the political, economic, etc. — all the other problems that this region has?

Daily: I think it’s a great question. I think at the individual level — if you have children, and very frequently they’re coming down with a febrile illness, they’re at risk for a bad outcome, developing seizures, death — And, we can eradicate this. We can take this off their list, of having a lot of challenges living in a resource-limited setting, I think we’d have a huge individual impact on families that are poor, because as Myles said, they’re really bearing the brunt of this problem. People who have more money, live in screened homes, and they’re able to take the anti-malarials and have good health care. So I think you’re right, the person on the ground, who’s at most risk, this would have a huge impact.

And then there’s been a lot of modeling about how much money could be saved. Perhaps a company would say, great, I want to come to your country and set up my company here, and you’ve eradicated malaria. Now, my workers are not at risk for getting malaria. So I think in terms of development; this is development, and it definitely would help that, as well. There’s a lot of oil companies in Africa, and they’re bringing non-immune workers who are at high risk for bad outcomes. So, I think you’re right. I think, economically, it would help with growth.

Akabas: One of the organizations that’s interested in treatment for malaria is the US military. Because years ago, when they were starting to put a stabilization force into Liberia, at the end of the Liberian Civil War, they had 600 US marines on transport ships offshore. And when they were supposedly taking their anti-malaria prophylactic drugs, they landed, and within two weeks, 200 of the 600 were back in the United States with fulminant malaria, because they hadn’t been taking their medicines. So, it’s a large risk for people who go to Africa, both to work, or for military adventures.

Campano: There’s something poignant there, that concerns about 600 American soldiers who had —

Akabas: Well, when you need the soldiers as your stabilization force, and one-third of your stabilization force is incapacitated within two weeks of arrival, you have a serious problem in being able to stabilize the situation to allow the African Union forces to come in, and replace them.

Campano: Wow.

Dr. Myles Akabas, speaking with Dr. Johanna Daily, our Technical Director, Jean Kremer, and me, at Albert Einstein College of Medicine in New York City.

In Part III of The Malaria Mystery, Myles and Johanna speak about the future of the fight against malaria — and what motivates them, personally, to keep working to stop this global disease.

The conversation continues at thebestmedicineradio.com. You can read a transcript, leave your comments, and learn more about the guests and resources mentioned on this program.

The Producer of the Best Medicine is Linh Tang, the Marketing and Technical Director is Jean Kremer, the Content Editor Evan McWilliams, the theme music composer Tim Hoyt, and the graphic designer Gabe DeSanti. I’m Erik Campano.  This program was originally broadcast on July 6, 2015. The Best Medicine is a production of WKCR 89.9 FM and WKCR HD-1, Columbia University in the City of New York.

The transcript of Part III of this program will be available shortly.

About the guests:

Myles Akabas, MD PhD is Professor in the Department of Physiology and Biophysics, the Department of Medicine, and the Dominick P. Pupura Department of Neuroscience, and Director of the Medical Scientist Training Program at Albert Einstein College of Medicine of Yeshiva University in New York City.

Johanna Daily, MD is Associate Professor in the Department of Medicine and Department of Microbiology and Immunology at Albert Einstein College of Medicine of Yeshiva University in New York City. She has treated malaria in the field in sub-Saharan Africa.

Both guests study the physiology, treatment, and epidemiology of malaria.

About the image:

Johanna Daily researches pathogenesis and drug resistance in the malaria parasite Plasmodium falciparum at, among other places, the Albert Einstein College of Medicine’s Global Health Center in Malawi.

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