Pratik Shah – TRANSCRIPT
I’m going to talk about something we cannot see, and we’re going to visualize it today together. So let me start with a very simple question about who we are.
As a microbiologist and as a geneticist, as a biologist, when I look at all of you right now, I see one human, with 30 trillion bacteria inside you. That’s right, at this very moment, all of us are carrying 30 trillion bacteria. They are invisible, they are amazing, they do stupendous things for us. They help us digest our food, they help us act as sentinels of our immune system, but we never see them.
Ladies and gentlemen, meet your microbio. What we know about bacteria and infectious diseases is the dark side of this interaction we have with them, which is commonly known as disease, and we all are familiar with epidemics of plague, cholera, and right now the ongoing pandemic of Ebola that’s going on in Africa, and in our country a little bit, too. So how do these relationship shift from being 30 trillion harmless bacteria to making us sick? And what can we do? Throughout history we have been combating bugs in different ways, and in the 20th century we discovered something called antibiotics. Antibiotics are these small molecules of drugs that you take, you eat, or you inject to kill the bacteria in your body. Unfortunately, they end up killing both the good and the bad, and that’s a problem. While we were innovating, bacteria were innovating too.
They were like, “Oh, OK” So what they did is they became resistant to almost all the antibiotics that we have I had a shoulder surgery five years back, and when I talked to my physician after coming out of surgery, the list of antibiotics I was put on was crazy; I was like, “Wow!” Then he, or she, at that point, they both told me that this is the current state where many bugs that we have now are not treated with these antibiotics that we have.
And the numbers are staggering: every year, 69 million kids die before they reach their fifth birthday. Out of these children, approximately 2 million kids die due to pneumonia and diarrhea, and these are infectious diseases. If you see, there is no Ebola on this slide. We need to start a conversation about managing infectious diseases better in our world that we live in.
President Barack Obama in September of this year issued an executive order, and the order states that scientists, innovators, community members like you, all of us should come together and brainstorm for a better way to manage infectious diseases because our current arsenal of drugs which can treat infections has been depleted. To solve these things, there are a couple of things we need to know. The first thing we need to know is that we will have access to a patient whom we will call John. John consistently falls ill because he drinks contaminated water, and gets diarrhea. And before we leave this room, we’re going to make sure John gets better.
That’s the task for today. Diarrhea is a serious disease. It kills approximately 2,000 kids every day. Let’s simulate a quick diarrheal infection in this room, quickly. If you were in John’s body right now, and these were the walls of John’s intestines, and all of you were bacteria, there were two things you did when you entered John’s body.
The first thing you did is you grabbed a seat; that’s what you did when you entered this room. The second thing you did as soon as you entered is you looked for food. And that’s exactly what infectious agents do: they get into our body, they find a place to park themselves, and they start eating. These are usually called dietary requirements of infectious agents. As a microbiologist, I am passionate to not kill bacteria first, before we understand what they do to us.
Till now, we have been killing them without understanding what they do, so let’s change the approach a little bit here. So this is John, drinking contaminated water, and this is you in John’s guts, coming in, you grab a seat, and John’s body provides you with this amazing food that you love. The bugs eat these food molecules that John’s body naturally provides them, and they become virulent, pathogenic, and they cause John diarrhea, obviously I decided to intersect into this problem in a different way, I wanted to understand what other food sources our body provides to bacteria when they cause infection. The technology I used to understand that is called metabolomics.
What metabolomics does is that it basically allows you to take any biological sample, infected sample, from a patient, from an animal, and lets you understand, get a peek or eavesdrop into the conversation that’s happening between a patient and a bacterium, and understand what are the food sources that the body is producing when we are sick. These food sources are usually called metabolites. These are the food sources that the bugs get when we get infected. With this information, I was able to build a Google map of all the metabolites you get when you are sick, – in the context of diarrhea and a couple of other infectious diseases – and these are the metabolites your body produces once you get sick. Apparently, humans had been dealing with bacteria before we invented antibiotics, right? Antibiotics in the 20th century.
It turns out when you’re sick, your body produces two different kinds of metabolites. The first metabolite your body produces are these blue ones which are called pathogenic metabolites. These pathogenic metabolites, when the bugs eat them, produce millions of molecules of toxins, and these are the toxin molecules that the bugs produce, and you get sick.
On the other hand, your body also produces millions of molecules – small amounts or trace amounts, depending on the infection – and these are the green metabolites – just colored here for understanding – that the bugs have evolved not to eat, they’ve learned to ignore and not eat them, or learned to circumvent themselves from these metabolites. So I did an experiment in the lab: what if we make these bugs eat these non-pathogenic or these other metabolites which they usually don’t eat? The answer was: when they eat those metabolites, they basically become avirulent or nonpathogenic.
In other words, they turn their toxin production down More toxin, disease; less toxin, less disease. So what we have is that nature has programmed us and bugs to have this conversation, and the conversation basically is: what do bacteria eat when they cause disease? Usually they eat the foods which make them pathogenic and make toxins. Sometimes, we can change these interactions by making the bugs eat things which sometimes make them nonpathogenic. So this is the handle we have on John.
Now let’s try and cure John, OK? So, John has diarrhea, and we’re going to see what we can do to help John. This is the second experiment I did in the lab. I reasoned if all of you are bacteria in John’s body, you come inside this room, you are expecting pathogenic metabolites, and this is what you’ve been eating, let’s assume that’s called steak. What if, when you walked into John’s body, we make John give you the other green, nonpathogenic metabolites? Let’s call them salad. So I said: “OK, let’s see what happens to John.” These are not steaks and salads, this is for the purpose of the talk, these are organic molecules. You guys are smarter than me, so I’m assuming you got that. So you did that, and basically what happens is – I was surprised – I failed miserably. The bugs wouldn’t eat them, they would not like them It’s like training a pet: they’re like, “No, No.”
So finally, after a lot of screening, a lot of screening, I identified a few metabolites which I thought would work. If those would work, then let’s see what happens to John. Does he get better? Does he get ill? What happens? Here’s John, again drinking contaminated water, this is you guys eating steak, and we flush it, and we give them these new metabolites. The bugs don’t know, they’re eating them, they don’t like them, in the real sense they become nonpathogenic, they turn the toxin production down, and they start exiting John’s body in noninfectious state, and John is happy. There are a couple of things I hope you took from it.
A: we did not kill them. We did not kill them. Up till now, we have been killing them, and this is a concept that we need to think about, that infectious agents usually can be trained, can be modulated, their diets can be changed. What I’m thinking, and what we all should think, is there a way we can intersect into this problem of infectious diseases by providing bugs, or training them for the new generation of food sources? These food sources will make the bugs avirulent or nonpathogenic versus killing them, and after they’ve become avirulent or nonpathogenic, they are trained to exit our bodies in a way that is safe for us to pass them out. Let’s assume that in the future we design a system which I’m calling at this point ‘on demand food service for bugs’.
The science behind this is really interesting. The science is that basically, when you’ve got an infectious disease instead of coming back with an antibiotic and killing the bugs, the first or the front-line therapy in the future should be and could be understanding and managing the infection by training the bugs, by giving them food sources which, instead of making them pathogenic, first make them nonpathogenic, noninfectious, and then, if required, come back with antibiotics. This concept allows us to use the antibiotics in a more rational way. It buys us time, basically to look for better antibiotics which we are not able to find, and this allows us not to go back and start killing them all over again, because we did that 50 years ago, and right now they are resistant. As the drawing board has been wiped clean all over the world with scientists, and business and industry people looking for more drugs, this is a new approach where basically we have an opportunity to fix this problem the right way for once and hopefully for a long time.
Because once we’d discovered penicillin, we stopped looking. And the bugs discovered penicillin too, after 50 years, and they were like, “Hang on I got a problem.” Then a couple of take-home messages I want you to think about: First one, that dietary needs of an infectious agent can be used to design novel antimicrobials. Second, a large scale deployment of these things is possible. We humans already have a network in place. Do you eat fortified wheat at home? Yes Do you eat salt with iodine in it? Yes.
So we already have a huge network of fortified foods rolling out in our communities, but up till now, these fortified foods only helped our health. You drink vitamin water, you get vitamins in your body, but the bugs have largely been ignored. The other thing I’m working on is the next generation of oral rehydration salt solution. This is given to patients who have diarrhea like John. But all that oral rehydration salt solution does is replenish the salts and the metabolites in your body that you loose while you have diarrhea, it does nothing to the bugs.
The bugs are just using John’s body as a vehicle. The next generation of oral rehydration salt solutions will hopefully include these nonpathogenic metabolites that can be incorporated as a front-line therapy before you get antibiotics. I want all of you to think about these things and discuss them, and see if there are novel ways we can intersect into this problem of antibiotic resistance because if not now, in the next 50 years, you’re going to face it. Thank you.
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