Wonder Bugs

Wonder Bugs

Caltech medical microbiogist Sarkis Mazmanian’s pioneering research on the curative powers of good bacteria earned him a 2012 MacArthur “genius award.”

By Bettijane Levine 01/03/2013

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Sarkis Mazmanian is not a household name, and the 39-year-old research scientist scoffs at the thought that it might someday become one. But if his groundbreaking research at Caltech continues to produce breakthroughs in potential disease 
controls and cures, he may one day be up there in the pantheon of scientists who have helped conquer major diseases.
Mazmanian recently won a prestigious 2012 “genius award” from the John D. and Catherine T. MacArthur Foundation, a fellowship with an unrestricted grant of $500,000, given to “individuals of exceptional merit who show promise of continued creative work,” according to the foundation’s website. Mazmanian certainly fills the bill. He is a Caltech medical microbiologist and professor  whose research has focused on microbes, which, he says, most people think of as “insidious little creatures that only cause disease.” 
But Mazmanian believes otherwise and started working more than a decade ago to prove a long-held belief among scientists, that there are good bacteria as well as bad ones — and that certain good ones might just be a source of cures for all sorts of autoimmune and allergic disorders, and possibly some neurological diseases and cancers as well.  Although scientists had long known there were trillions of species of so-called good bacteria living in our intestinal tract, none of those species had ever been specifically identified or proven to be beneficial. 
Mazmanian has done just that. His lab was the first to identify and isolate specific beneficial bacteria, and demonstrate that these organisms regulate the human immune system and provide protection from certain diseases. The absence of such bacteria, he hypothesized, was what caused these diseases. It was a great conceptual leap, and his results have transformed scientific research in this field. He has already cured multiple sclerosis and inflammatory bowel disease in lab mice, by giving them specific bacteria from human intestinal flora. His lab is working to produce bacteria-based therapies that may someday be commonly prescribed for individuals diagnosed with diseases currently with no cure. So far, he says, his experiments with lab mice suggest that asthma, type 1 diabetes, Crohn’s disease and multiple sclerosis may eventually be cured with drugs made from human gut bacteria. Of course, there’s a long way to go before such cures will be available to people, he says, “but the plan is to proceed to human experiments” and to eventually market drugs like those being developed in his lab. 
Mazmanian theorizes that the increases in certain illnesses over the past 50 years correlates directly with the increase in human exposure to all sorts of antibiotics and chemicals: not just drugs, but also foods, personal hygiene products like soap and toothpaste, household cleaning products — even toys, can be embedded with antibiotics, he says.    
This over-the-top exposure, he believes, has eradicated some  good organisms that have always lived in human intestines, “organisms that have evolved with us for millions and millions of years,” he says. Without the immune protection they were meant to provide,  there has been an immense increase in certain illnesses that were not so prevalent before. His answer: Cure the illness by replacing the natural gut organisms, which nature has provided for immunity, and which should be there but aren’t. 
Mazmanian’s research helped lay the groundwork for the National Institutes of Health’s Human Microbiome Project (HMP) involving 200 scientists at 80 institutions, who are identifying “the microbial communities found at several different sites on the human body, including nasal passages, oral cavities, skin, gastrointestinal tract and urogenital tract, and [analyzing] the role of these microbes in human health and disease,” according to the HMP website.

You gambled by taking a research path not traveled by scientists before. Was there a eureka moment when you said, “Aha! I will study the beneficial effects of  bacteria while the rest of the world studies the bad effects?”  
Yes.  I can pinpoint the very moment it happened, about 11 years ago. I was a graduate student studying bacterial pathogenesis, or how bacteria cause infectious diseases. At that time, 99.9 percent of microbiologists interested in human-associated microbes were all studying pathogens that cause disease. It made sense, right? 
Then I read an article about all these bacteria that live in our intestines, and the enormous magnitude and diversity of these organisms. I became fascinated and went into the literature. I found there was virtually nothing known about any of these organisms. Nothing at all. That was the eureka moment. I thought, I have to study this because it’s so far off the beaten path, so off the edge. I jumped in with both feet and am still studying the area to this day.

You’re saying no one knew about these bacteria?
No. People knew for 100 years there are bacteria in our intestines. But what are they doing? Why are they there? More fundamentally, why does our immune system tolerate them and not attack them? Think about it: If you get just 10 cells of salmonella or E. coli, your body mounts a very vigorous immune attack against them. So how is it that we peacefully coexist with these gut organisms? This was not investigated.

Did you have to prove there are good bacteria in human intestines? Wasn’t it already taken for granted by scientists?
A good analogy would be likening this to life on other planets. You talk to astronomers and they all, mathematically, would say it’s extremely likely there’s life on other planets. From a purely theoretical point of view, with the billions and billions of planets there are, and all the chemical reactions going on, for life to have originated on only one of those planets is highly unlikely. So there’s probably life on other planets, but we’ve just never discovered it, so we can’t prove it.
In the same way,  the whole world can believe it’s highly likely that some bacteria are good for you. But if there’s really no proof of it, then it still remains theoretical. What we did was show the first example of these good bacteria, and by showing that first example, it opens the possibility that this is true, and that it can be demonstrated again and again. So yes, everyone did believe there were likely good bacteria, but no one had ever proved it before. We were the first.

Did you know what you were looking for?
We were looking for needles in the haystack. There are literally thousands and thousands of species of bacteria in the human gut, and they are as different from each other as humans are from earthworms. And only a few of them are going to be therapeutic. We found a couple. We characterized them… and this was sort of the basis for the [MacArthur] award. Not just the experimental validation, but the conceptual event.

What was your hypothesis going into your experiments?
The absence of good bacteria is a risk factor for disease.

And your truly groundbreaking work was proving that these good bacteria somehow protect or activate the human immune system, and that the absence of them causes disease?
Yes,  that’s correct.
You’ve said the good bacteria have existed in the human body for thousands of years. Why have they suddenly gone missing in some of us?
No one knows exactly, but it possibly started with the invention of penicillin, which was called “the magic bullet.” By the late 1950s and early ’60s, antibiotic use was way up. By the ’70s and ’80s, it was prescribed like candy. And as we tried successfully to eradicate the bad bacteria, the good bacteria were the collateral damage.

You’re saying that overexposure to antibiotic drugs has caused an increase in autoimmune and allergic disease?
I would never advocate against the use of antibiotics. Civilization has benefited immensely from them. Limiting them would make us sick again with infectious diseases. Clearly they’ve caused a huge decrease in infection. And because of antibiotics we live much longer now than we did 50, 60, 70 years ago. 
But remarkably, in the last 40 or 50 years, the incidence of autoimmune and allergic disorders, such as inflammatory bowel disease and multiple sclerosis, has increased. In an era where infectious diseases are going down, noninfectious allergic and autoimmune diseases are going up.

What’s the significance?
Perhaps there’s a correlation between these two events. And that is what really got us into this work. Changes in our lifestyle in the last 50 or 60 years, including exposure to antibiotic drugs and to the antibiotics in food and in household cleansers and hygiene products, such as toothpaste and soap, even children’s toys — along with exposure to chemicals in food preservatives and in pesticides — all may have played a part in affecting our immune system. Add to that the western high-fat, high-sugar diet. As a 
scientific community we don’t know which of these factors are the ones affecting our gut microbes. I think there’s a consensus that each of the factors incrementally, or maybe in the aggregate, has a huge effect on the increasing prevalence of many disorders.   

So overmedication isn’t the biggest worry?
The current estimate is that 70 percent of all antibiotics produced go to livestock, not to humans. The animals are given antibiotics to fatten them up. The less sick they are, the more weight they gain, and meat is sold by the pound. Industry quickly figured it out: Let’s just supplement the feed with low levels of  antibiotics and we’ll get fatter cows, chickens and pigs. I try to eat organic meat and foods.

What other precautions do you take?
I try to stay away from foods with preservatives in them. It’s not just antibiotics that kill the gut bacteria. Chemical preservatives do the exact same thing. I try to stay away from foods with pesticides and wash foods very, very well, because antibiotics and pesticides are sprayed onto them. Things like household dishwashing detergents have very potent antimicrobials in them. I stay away from those and use plain soap.   

Do pesticides have antibiotics?
Indirectly. They’re indirectly antimicrobial, because they prevent insects from colonizing or eating the food, and the insects themselves are covered with bacteria, or affect the microbial ecosystem. It’s a different conversation than the one we’re having, but pesticides are shown to have an effect on how much bacteria are on foods themselves.

You haven’t mentioned cancer as a possible disease that might benefit from research in your lab.
I would say we are just beginning to appreciate how gut microbes affect colon cancer in particular. We cannot generalize this to all cancers because the data isn’t there. Even for colon cancer, the data are still preliminary. Not to say there isn’t evidence, but it is not definitive.

 What is definitive from your research so far?
In experimental animals  — we have not yet moved to humans, but that is in the plan — we have identified a bacterium and a molecule from that bacterium that treats and cures inflammatory bowel disease and multiple sclerosis. So in mice we can cure those diseases using nothing but gut bacteria. That is the conceptual leap here. We’ve shown that you can take a bacterium from the gut of humans and put it into mice with multiple sclerosis or inflammatory bowel disease, and we can cure the disease. Our lab work actually shows that the absence of organisms is a risk factor for disease, and that giving those beneficial organisms which have protective effects to people may be a therapy for four diseases: asthma, type I diabetes, multiple sclerosis and Crohn’s disease.

How did you  medicate the afflicted lab rats?
With a supplement that restores good bacteria during and after an antibiotic regimen.

What kind of supplement?
We’re talking about pharmaceutical-grade drugs, but the drugs themselves are not chemicals that were synthesized in a laboratory. The drugs are molecules made naturally by our own gut bacteria.

Does any lab make such drugs?
Our lab makes them. We extract the bacterial molecule which the bacteria produces and synthesizes. We don’t make the molecule; we purify it directly from the bacteria.  
No one has developed this as a therapy yet. It’s in the process of being developed. We have patents. But as you can imagine, it’s difficult to get pharmaceutical firms to invest in developing these things. And there are many hurdles to go through with the FDA to get licensed to sell a pharmaceutical drug. That will require a lot of effort but we are starting on that path.

What about potential similar cures for neurological diseases and autism?
There’s emerging evidence for those, some reason to believe there might be an association, but nothing strongly definitive just yet. 

Does your lab deal only with intestinal tract bacteria? 
 Yes. Just the gut.

What is your most optimistic fantasy for where all this could lead in the future?
This is all speculation: My hope would be that we, as a scientific community, will  identify organisms, microbes, that are specifically beneficial to various human ailments and diseases. So one can imagine that a specific microbe may be effective in controlling multiple sclerosis, another microbe might be effective controlling cancer and yet another would control heart disease and so on. And that some day we will go to the doctor and get a diagnosis for disease or ailment X, and the doctor will prescribe a pill that will not contain a chemical, not contain a compound that was synthesized in a laboratory. It will contain bacteria, the specific bacteria meant to cure your specific ailment.

Will that bacteria have been obtained from the human body?
I believe that’s the first place to start. Because these are the organisms we have evolved with for thousands of years, the ones that have learned to network and interact with us on a molecular level — talk to our cells and interact with the receptors of our cells. Those organisms are more likely than any others to trigger the beneficial effect. 

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