Do Mosquitoes Offer Potential to Fight Human Disease?

Ira Pastor, ideaXme longevity and aging ambassador and founder of Bioquark interviews Dr. John (Jose) Mejia, MD and founder of Ectocrine Technologies to evaluate mosquitoes as a drug delivery system and their saliva offering a potential cure for human disease.

Ira Pastor comments:

Could we eradicate many diseases with Mosquitoes?

The common #mosquito , while being responsible for up to a million human deaths each year, may paradoxically also hold biochemical secrets in its ectocrine secretions, to cure diseases that affect hundreds of millions of people around the globe.  Examined here, could the common mosquito be more friend than foe?

Mosquito eradication programmes a lost opportunity to fight other human disease?

Mosquito eradication programs (i.e. @gatesfoundation & Google), while offering a solution to the millions of deaths each year from mosquito born diseases, ignore the critical immuno-pathological role that such creatures have played over hundreds of millions of years as they propagated their beneficial biochemical signals in invertebrates, fish, amphibians, reptiles, birds, mammals, and humans. 

Note: Ira Pastor and Dr Mejia have formed a collaboration agreement starting December 2018.

Ira Pastor: [00:00:00] I am Ira Pastor, exponential health ambassador for ideaXme, the show that highlights thought leaders and big thinkers who generate the ideas of the future. We have a really exciting show today.

[00:00:14] Aging is an extremely complex process that is controlled by a series of nested hierarchies that expand from
the very small genes, proteins, gene regulatory networks and on up through more complex physiological regulatory
networks, bringing in forces of mechano-transduction and membrane potentials, hydro dynamics, tissue tensegrity.
And the, of course, beyond the body into the organism’s complex external micro environment.

Ira Pastor: [00:00:48] Today, we are going to take a bit of a journey to another level of this hierarchy to something that we will broadly call the macro-biome. Now, while many in the public are familiar with biotech terms like genomics and proteomics and monoclonal antibodies, there are other terms that they may be less familiar with, such as ectocrine dynamics, inter kingdom signaling, semiochemical communication, and induced phenotypic plasticity. A lot of these are complex ways to talk about one thing: how living organisms of one species can signal and affect the health and wellness in a positive way of another species. And today we have a fascinating guest who is really at the epicenter of this. 

Could mosquitoes help us eradicate other diseases?

Ira Pastor: [00:01:35] We have Dr. John Santiago Mejia. Dr. Mejia is a medical doctor who spent the last few decades working in infectious disease, immunology, parasitology, studying a wide range of disorders such as malaria, Chagas disease, Leishmaniasis and really spanning a wide range of human pathologies. Yet interestingly today, as we get into this topic of the microbiome paradoxically one of the species that we’re going to be focusing on in this discussion, the common mosquito, which you know nowadays is considered as one of the most deadly organisms on the planet responsible for three quarters of a million deaths around the world may very interestingly and paradoxically hold biochemical and pharmacological secrets for addressing disease and beneficial applications in hundreds of millions of patients around the world. So, with that brief introduction. Welcome Dr. John Santiago Mejia to the show. 

Dr. Mejia: [00:02:39] Thank you for the invitation and for arranging this discussion. I believe this is a subject that needs to be debated. 

Dr. Mejia: [00:02:49] What I’m going to be describing is a catastrophe, a global catastrophe. A number of interventions that are currently being implemented to control diseases are seeding the ground for a much bigger problem. I will give you some details about this in our discussion here. 

Ira Pastor: [00:03:15] That’d be great. But let’s start out with you. Typically, we hand the mic over at the beginning of the show. We give you the floor to just talk a little bit about who you are, where you grew up, how you got into science and medicine and became interested in Parasitology. I’m sure the audience will find it very interesting to hear about your background. 

Curiosity and solving the unknown

Dr. Mejia: [00:03:38] I am from Colombia. Ever since childhood, I was a very curious. I loved to read. And very early on I realized that I had an interest in what is NOT known. My learning was based on that perspective; of looking to solve the unknown in one discipline. Medicine seemed the obvious choice. So, I got into medicine, not because I wanted to see patients or be a surgeon but because I realized that there were too many questions that needed to be addressed in the field. It was fertile ground for research and of course still is!

Solving problems in neglected tropical diseases

Dr. Mejia: [00:04:24] I enrolled in medical school in Columbia. I studied there for seven years. After that, I had the opportunity to work in the laboratory of a very well-known scientist in Colombia who was developing a vaccine against malaria. So, I started learning everything about the parasite and then vaccine development. In those days, I was trained to be a rheumatologist but then they sent me to the jungles of Colombia looking for patients with malaria. I was able to see the miserable conditions and poverty within the Indian and black communities in the jungles of Amazon. That was the point at which I committed myself to concentrating on solving problems within the neglected tropical disease arena. I thought that I could make a difference.

Experimental models for antigen development

Dr. Mejia: [00:05:36] So, I changed my focus because I wanted to help. And then in doing so, I went to Mexico to study very serious neglected diseases and viruses. I started with antigen vaccine development. My experimental models were very similar in approach to those used in working with malaria. 

Dr. Mejia: [00:06:03] I then received an offer from a Medical Center here in Boston. There was an opportunity to work with Chagas Disease, which is the only totally Latin American disease. It only occurs in the region, from Mexico down to Patagonia, nowhere else on the Planet. 

Dr. Mejia: [00:06:43] Then I received an offer from a biotech company to work on the complex and challenging parasite Filaria, responsible for very serious health problems across the world. 

Working with Dengue mosquitoes

[00:07:06] Thereafter, I worked with Dengue mosquitos. It turns out that the larvae, the infected larvae stay dormant inside the infected mosquito with Dengue. 

Dr. Mejia: [00:07:55] I was chasing the antigens against the parasites [5.7] and it had been proven until that time to be impossible. Thereafter, I completed another post-doc in Colorado. This time, it focused on a different parasite, the sand fly parasite, a very serious world-wide problem which was getting worse.

It was challenging. I had the unique opportunity to see the problem of vaccine development from a very different perspective. None of these vaccines to this day work at all. There’s no viable vaccine against Chagas or Filariasis diseases.

Later in my career met Dr. Richard Titus who was a pioneer in developing solutions to fight these diseases. He invited me to work with him on a new approach developing effective vaccines. 

The potential medical use of anthropod saliva

I learnt that arthropods inject and deliver saliva along with the pathogens. I was taken aback by this revelation. I was not even aware that mosquitos could salivate. And so, it turns out that all these hematophagous arthropods need to actively develop a very particular cocktail of salivary molecules, to be able to steal the blood of vertebrates. This opened a page in my book, gave me a new perspective. 

I have dedicated my life to study arthropod saliva and the biological underpinnings of its functional potential, in both the context of infectious diseases and on studying the context of chronic non-communicable diseases.

The Missing Piece of the Hygiene Health and Disease Puzzle

Ira Pastor: [00:09:57] This is really a fascinating background for the next part of the story because you were involved in these different research paths dealing with a lot of nasty organisms. Research hat dealt with a lot of quite infectious microorganisms, yet you then publish in 2014 as you were just mentioning when you changed your focus, or you had this added focus on saliva; a wonderful paper entitled Arthropod Saliva: The Missing Piece of the Hygiene Health and Disease Puzzle. Coming out of the pharmaceutical industry, I love pharmaceutical history. I am acutely aware, that most of the greatest discoveries that ever occurred in this space were not simply things that happened in the lab but were accidents or “eureka aha moments” that potentially opened a whole new pathway. 

The “aha moment” in discovering that the mosquito may be more friend than foe

Ira Pastor: [00:11:13] I would like you to talk about your “aha moment” that moment when you realized that “there’s something here”. Once we separate the nasty stuff, there is this potential treasure trove of other things present that the scientific community probably should focus on. Could talk about this? Your paper not only mentioned diversity, or this biologic diversity that we are missing but also, from some of your experience in the jungles and in some of the endemic regions of the world where you have these organisms some of the paradoxical things you saw between and endemicity and chronic disease. So, if you could speak a little bit about this “aha eureka” time? I am sure that the audience would really like it. 

A treasure trove in the saliva of mosquitoes

Dr. Mejia: [00:12:12] When I started working with the idea of targeting the saliva of the mosquito, I soon realized that there was a huge opportunity. It was theoretically possible to talk about a pan-arthropod vaccine. To clarify, the pan-arthropod vaccine would be one vaccine to prevent every single disease caused by these vectors from dengue to malaria.

Dr. Mejia: [00:12:44] It was and is an extraordinary opportunity. I have spent eight years on it, trying to figure out which are potential targets. I evaluated each one based on an experimental model that I had when I was working with 3 different species of different vectors and categories.

Fight human disease with mosquitoes and immunomodulatory molecules

Dr. Mejia: [00:13:19] As part of the process of studying the possibility of peptide segments, I realized that the clue was in the glycans. One of the fascinating things going back to your comment about pharmacology is that each species of arthropods, and remember arthropods are the most diverse taxa in the biosphere. There are more than one million species and many of them adapted to a blood meal type of diet. They have adapted over eons and eons to the changes in their mouth patch, The saliva is able to essentially neutralize and a whole set defense mechanisms, all of them actually anti-inflammatory molecules, anesthetics, immunomodulatory molecules.

A multi purpose vaccine to fight disease

Only by developing these forms of a complex formulation will we be able to neutralize something that is characterized by its very intrinsic redundancy. That is why it was so crucial to use mosquitos in development for a complex mix of molecules that simultaneously will inhibit and de-activate all these biological defense mechanisms.

As far as applications in disease control are concerned and the issue of redundancy, I was looking at an option and looking into peptides that work in the brain. I learned that from a protein perspective and gene perspective, the saliva from a tick is not very different from that of a mosquito or from a flea each particular group. Each taxonomical group, even the species develop their own recipe. So, going after the proteins alone didn’t make sense for the purpose of the pan-arthropod vaccine.

The immune response

I then entered into the glycan story. For people not very familiar with this cellular structure called the Golgi complex. It takes proteins and then puts some sugars on them in secretion of these compounds. I subsequently found that the Golgi system of arthropods are trapped.

A pan arthropod vaccine

We developed a very interesting system to evaluate those we develop a vaccination platform. We realized that the fundamental problem was that these sugars induce something called a TH1/TH2 bias of the immune response and so in essence it changes the nature and the character and the strength of the immune response at the bite site. And that makes perfect sense. The mosquito de-activates the defense system of the host. This process has been linked with allergic reactions in humans.

When I tried to get grant funding to pursue this further, it was not granted. It was argued that “you’re going to develop a pan-arthropod vaccine that induces allergies. How do you expect us to fund something like that?” I’m a fighter. So, I continued to delve deeper to understand more about this.

The missing piece of the hygiene health puzzle – to fight disease

More than 200 million people are infected in Brazil, India and other tropical areas.

During the course of my research, I was totally shocked to realize that not only mosquitos but 2-3 different groups of arthropods were working with the same molecule that is used by nematodes to de-activate the immune system and that are responsible for an eosinophilic response that actually deactivates the defense system allowing these parasites to live a long life inside the host. It is a striking example of convergent evolution. Then I said to myself, wait a second, arthropod saliva might be linked to something that ought to be special for hygiene hypothesis.

After the Second World War many countries eliminated ‘parasitic elements’ from the environment. They are now suffering from an epidemic of chronic disease, including multiple sclerosis and diseases that were not even on the radar in the 19th century. It occurred to me that there was a theoretical possibility that we needed the saliva of arthropods for something physiological. The fundamentals of the paper that you mention earlier from that.

“Exposure to arthropod saliva is good for humans” to help fight disease

Up to that point I was arguing that it is possible that the exposure of saliva of arthropods is good for humans and for human health. I want to make this very clear, exposure to an infected mosquito is always bad news. I am not advocating that we should be bitten by them but should we kill off the species? Nobody has evaluated this systematically. I argue that a healthy mosquito produces all these anti-inflammatory molecules, the anti-coagulants which are good for us. So there may be an argument to produce healthy mosquitoes.

A catastrophe when the honey bee declined

Ira Pastor: [00:21:30] Let’s dive a little deeper into that. There was a recent paper out of University of Queensland Australia about the expected decline in so-called entomofauna predicted this century, upwards of 40 percent of insects are potentially going to be gone. A couple of years ago, it was a catastrophe when the honeybee declined. 

Eliminating species of insects might represent a lost opportunity to fight human disease

Ira Pastor: [00:22:19] Organizations such as the Gates Foundation and Google Earth are trying to eliminate certain species from the Earth entirely and we’re not opposed obviously to getting rid of the ones that carry the nasty organisms. At the same time, we must realize that if they’re all gone and we miss this opportunity to tap into the wealth of pharmacologically active stuff we’re going to miss a major opportunity.  

Possible pharmacological agents to isolate from the saliva to fight human disease

Ira Pastor: [00:23:03] Take off your scientific hat for a moment and let’s move into the sort of pharmaceutical development realm for a moment. You Mentioned painkillers. You’ve mentioned anticoagulants and immunomodulators. In your paper you mentioned neuro peptides. Just talk a little bit about, obviously drug development is a long process it takes time to come out of the pharmaceutical industry, talk about some of the potential classes of pharmacological agents that you see isolating from the saliva, whether it’s mosquitoes whether it’s other organisms. What are some of the basic classes that you may see as good paths to follow with what we know today?

Cataloging the saliva of every single hematophagous arthropod on Earth

Dr. Mejia: [00:23:54] Dr. Titus together with Dr. Ribeiro created a whole catalogue of molecules. All that information is available through NCBI if any of you want to dig into it. This is fascinating work.

Going back to the idea that insects are a treasure trove, hundreds of potential molecules in that pipeline. Hirudin which happens to be an anti-coagulant is from leeches and is now available for clinical application that has proven very effective.

As mentioned, Dr. Ribeiro is working on anti-coagulates and the immuno- complement system with application, for instance, in transplant biology. There is so much potential, such as extracting solitary molecules for treating patients with anything from heart attacks to strokes to problems with the brain. 

I work with one vasodilatory molecule. It interested me because it has a resemblance to those in the pituitary gland. Just think about it. There’s a molecule in the saliva that binds to the pituitary gland, that begins to connect things.

Lets change our perspective towards the mosquito to fight disease in humans

I want to change the perspective. We should consider changing our perspective in relation to the mosquito, especially if we can guarantee that they are healthy and do not transmit a pathogen.

Precedent set for using organisms as therapeutic entities to combat disease

Ira Pastor: To summarise, evolution has perfected a cocktail. But you’re bringing up a very interesting topic I want to get into next because a lot of the audience, while they’re familiar with traditional drugs one thing that is a lot less well known is that in the United States the FDA in the past several years has approved many of what we call living organisms as therapeutic entities.

Leeches, helminth worms and maggots approved by the FDA

Ira Pastor: [00:29:29] Leeches, maggots and helminth worms are all approved in the United States by FDA as ‘medical devices’ for various conditions.

A beautiful drug delivery system

Ira Pastor: [00:29:59] We can isolate these pharmacological agents for one area of the pharmaceutical industry and find new pain killers and anticoagulants and auto immune modulating substances. But on the other hand, there are living organisms which you rightly say have been here several hundred million years. It’s been fighting everything along the way. It’s evolutionarily optimized as a beautiful drug delivery system. So, like the leech and the maggot and the helminth do you see possibilities in the future of developing clean mosquitoes as the therapeutic delivery vehicle themselves? Let’s talk about that. It’s something that we’ve discussed off line but I’m sure the audience would be quite intrigued to hear about your ideas. 

Low cost high efficiency pharmaceutical product from the mosquito

Dr. Mejia: [00:31:15] I agree with you, mosquitos offer potential as a platform to deliver vaccines. It’s a good thing to use them for vaccines on people. It is an ideal delivery vehicle for parenteral pharmacological agents. You don’t have to go through the traditional development process that you would for vaccines. But there’s a lot of issues about the antigen effect and there’s a disease that is not caused by the vaccines themselves, but by the adjuvants added to boost their efficiency. So that having a platform like this that can deliver low cost and high efficiency as a pharmaceutical to be introduced to a population of people would be ideal. We should consider engineering mosquitoes to produce some additional stuff for us.

Ira Pastor: [00:32:54] It’s truly a fascinating idea. When we think about what lies beyond the Earth, you think of all the things that they’re bringing up on the international space station nowadays to see what happens, whether it is salamanders, flat worms or tardigrades. I agree with you on that mosquitoes should be on a payload at some point. They’re connected to so many neural biologic systems and as we head off to Mars or even further afield, we need to think about the macrobiome which is keeping us healthy. 

From science to science fiction

Ira Pastor: [00:33:33] So, this has been exciting. As you know we like to transition at this point in ideaXme interviews from science to what we’ll call the science fiction realm. We ask everybody this question. Dr. Mejia, if I was to pull a time machine out of the closet and allow you to use it. You can go anywhere you want, travel to the past or future. Where would you want to go? Who do you want to meet? And what are you going to talk to them about?  

Attempt to understand motivations for humans to be violent

Dr. Mejia: [00:34:14] Well first, I have to say that while I was attending medical school in Columbia it was the years of Civil War and drug traders. It was a terrible cocktail. There was so much violence and so much blood. It was a shocking experience. It had a huge impact on me.

Dr. Mejia: [00:34:33] It was very revealing about human nature. So, for me, the issue of violence and trying to understand the human motivations behind it is important.

I would like to understand what motivates people to be violent, as humans, as a species. With that in mind I would love to have a chat with Jesus Christ. I would like to ask him one question that relates to the issue of violence and understanding it. 

Social intervention study

Dr. Mejia: [00:35:15] Why did he intervene in the Middle East and at that time? There were a lot of places that were in turmoil then, that is, where people suffered from violence and extreme depravity. Was there a particular form of violence that caught the eye of Jesus, God? What was the reason he intervened? I have thought about this a great deal. As a result, I have a hypothesis. I think there was a unique type of violence there at the time that in my opinion was so terrible, to such an extent that Jesus, God had to intervene. His sacrifice managed to essentially create a cultural transition. The sacrifice of Jesus Christ can be seen within the context of a social intervention study. 

Viewing “the larger holistic picture” to conquer disease in humans

Ira Pastor: [00:36:52] It was a pleasure having you on the show today. We hear so much in today’s scientific world about the reductionist view but viewing the larger holistic picture on the grander system is truly fascinating and necessary. I think the audience will really appreciate that. Dr. Mejia thank you so much for joining us today. This was a major pleasure. 

Dr. Mejia: [00:37:37] Thank you. 

Credits: text, audio and video interview, sourcing and research: Ira Pastor, ideaXme longevity and aging ambassador and founder of Bioquark.

The transcript above has been approved by both Ira Pastor and Dr John (Jose) Mejia. Some of the transcript has been edited to improve fluency. We have done as little as possible to change the original speech. Any questions: [email protected]

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