I recently had the pleasure of interviewing Rita Colwell, a “giant” in the field of microbiology and microbiomes, at the 2018 Precision Medicine World Conference in North Carolina. I asked Rita to tell us more about her work and discovery that intestinal infections may be more complicated that once thought and that the gut microbes we start off with may determine our risk of developing nasty infections.

Rita Colwell is a classically trained microbiologist turned geneticist. She describes the changes that the field of genomics (and microbiome science) has introduced to medicine and public health as fantastic. Microorganisms manipulate the world we live in and our health in profound ways that we are really just beginning to understand, partly thanks to genome sequencing technologies. One thing we have realized, however, is that our diet – including what and even when we eat – affect our health through our gut and the microorganisms living there.

Portrait of Dr Rita Colwell. Credit: Chaman Sond.

Portrait of Dr Rita Colwell. Credit: Chaman Sond.

“A lot of people, my daughter included, have had chronic problems with their gut – pain, bloating, etc.,” Rita said, when I interviewed her at the Precision Medicine World Conference at Duke this year. “Many of us have been told that it’s all in our head, when it’s really all in our gut, the little bugs in our gut. With what we know today, we might be able to control and manipulate communities of microorganisms in our gut without harsh chemicals or drugs, but rather simply through diet.”

Read more: How Your Gut Microbes Unlock a High Fiber Diet

From Enemies to Friends

Rita hasn’t always been aware of the importance of nourishing the “good” microbes in our gut, for example with a high fiber and largely plant-based diet, to improve our health. When she first started her journey with microorganisms, she was mostly investigating aquatic microbes, including pathogens, that when present in water can make us sick. Her studies were in the field of aquatic microbiology as a PhD student at the University of Washington. She is famous for her work on Vibrio cholerae, bacteria associated with the diarrheal disease cholera. Rita has saved countless lives through her work tracking the spread of cholera, identifying environmental signatures associated with cholera epidemics, developing water treatment methods that can prevent individuals from contracting the disease from contaminated water sources, and predicting outbreaks. Rita’s illustrious accomplishments as a scientist also include serving as the eleventh director of the National Science Foundation and receiving the National Medal of Science from President George W. Bush in 2006.

Rita’s work has extended into public health through detection and prevention of potential epidemics and identification of risk factors for various infectious diseases. She has worked in Bangladesh since 1975, at the International Center for Diarrheal Diseases Research, identifying sources and risk factors of cholera.

Rita has also been involved in research using satellite sensing to predict environmental conditions that may lead to outbreaks of infectious diseases such as cholera. Her team predicted, just a few months ahead of time, the outbreaks of cholera now underway in Yemen. These predictions include information about approximately where and when the outbreaks are at high risk of occurring. Aid organizations with access to this information from Rita and her team have been able to intervene and as a result significantly reduce the number of severe cholera cases that might have otherwise occurred.

Only more recently has Rita come to realize that preventing and treating infectious diseases may be much more complicated than dealing with single pathogenic microorganisms.

Sequencing the Good, Bad and Ugly Bugs

After a series of bioterrorism attacks following 9/11, Rita, then Director of the National Science Foundation and now a professor at the University of Maryland and at the Johns Hopkins Bloomberg School of Public Health, had a new idea for rapidly, accurately and actionably identifying pathogens and tracking microorganisms in the environment. This idea led her subsequently to found CosmosID, a bioinformatics platform and next generation sequencing services laboratory for microbiome research and diagnostics.

As Director of the National Science Foundation through 2004, Rita chaired an interagency advisory committee for the FBI and the CIA to help track the perpetrator of the 2001 anthrax mailings. It took experts six years to use genetic information to successfully complete comparative analyses that led to the source of the anthrax spores. This genetic information came from anthrax spore materials found on victims and in letters sent by the perpetrator. Investigators eventually identified the source and perpetrator of the anthrax mailings based on genetic signatures of the microorganisms derived from the various materials.

While the investigation was ultimately a success, Rita thought microbiologists and geneticists should be able to accomplish identification and characterization in a significantly shorter time frame.

“I decided it was time to change identification and characterization to six minutes, not six years,” Rita said. “At the time of 9/11, we didn’t have a database of microorganism genomes, nor much in the way of bioinformatics. We had to build the airplane as we were flying it, so to speak, because we had to begin to build a database of the genomes of serious pathogens. That became the basis of our ability to identify and track the source of serious human pathogens like the anthrax bacteria, as well as agricultural pathogens. Knowing the precise sequence of each strain of a pathogen like smallpox, for example, is important for tracking the source of an infection.”

“The (Anthrax) investigation also accelerated development of a nascent scientific field, called microbial forensics, involving a series of laboratory tests to pinpoint the genetic identity of a microbial agent used for nefarious purposes. This field grew out of the multidisciplinary areas of genomics, microbiology, and forensics, among others.” – National Research Council

Rita and colleagues now have developed algorithms to detect microorganisms in a range of samples, from stool to urine, blood, sputum, air, food and soil, via extraction of nucleic acids including DNA and RNA. At CosmosID, Rita has helped develop an elegant database of over 165,000 highly curated microorganism genomes, with which she and colleagues can diagnose infections or identify the nearest neighbor of an unknown pathogen, as well as reconstruct the pathogen genome. Rita and experts at CosmosID use their algorithms and microorganism genome database for various applications from healthcare to water treatment. For example, they help water agencies detect the presence of microorganisms and certify treated water as being free from harmful pathogens. CosmosID also uses Bayesian statistical methods to determine the accuracy by which they’ve determined the presence of any given pathogen.

Microbiome in human gastrointestinal tract. Credit: Marcin Klapczynski.
Microbiome in human gastrointestinal tract. Credit: Marcin Klapczynski.

Vibrio cholerae, Precision Medicine and Public Health

Rita was a key player in determining the first complete genomic sequence of Vibrio cholerae, as published in Nature magazine over 18 years ago. Back then, completing such an analysis of an important pathogen was a huge deal. Today, experts have sequenced the genomes of thousands of pathogenic microorganisms. This work and the rise of next generation sequencing technologies and bioinformatics platforms have allowed microbiome data to be applied in fields of precision medicine and public health.

Rita and colleagues at CosmosID are today working with physicians to better inform patient treatment based on precise information about microorganisms present in the gut or otherwise contributing to infection in an individual.

One Disease, Many Bugs

“We’ve found that almost every infectious disease thought to be caused by a single pathogen is in reality associated with a mixture of microorganisms,” Rita said. “Until now, we just haven’t had a chance or any scientific methods that would allow us to identify and characterize rapidly all of the bacteria, fungi, viruses and parasites associated with a given infection at the same time, and within hours, not days or weeks.”

But now, we can. With modern genomic sequencing technologies and growing microorganism genome databases, we are able provide a much more realistic picture of which microbes are in the gut, on the skin or in the mucous membranes of an individual at any given time. Rita has become a leader in the field of using genetics to identify diverse microorganism communities in and around us that are associated with health and disease. She has helped develop methods for rapidly isolating genetic material from microorganisms in our environment as well as in and on our bodies and using these nucleic acids to identify and diagnose inflections, for example.

“We are now able to determine exactly what pathogens may be present as mixtures rather as single pathogens, and potentially what other organisms that aren’t normally pathogenic may be creating problems when pathogens are introduced,” Rita said. “We are in a whole new era of understanding poly-microbial infections.”

Rita and her colleagues have recently developed and tested the hypothesis that what we call cholera is not necessarily caused by the Vibrio cholerae bacteria alone. There is a forthcoming paper by her group showing that in fact, acute serious diarrheal diseases collectively known as cholera today might involve a range of different microorganisms. Vibrio cholerae may not even necessarily be involved in the disease we consider to be cholera.

“We have learned in a five-year study with the National Institute of Cholera and Enteric Diseases, based on a large number of stool samples from patients coming into the cholera hospital with symptoms of cholera, that patients who present with severe diarrheal disease frequently had more than one pathogen, sometimes as many as four to ten different pathogens,” Rita said. “And these weren’t always just bacterial. They were often viruses, for example rotavirus and norovirus, a fungus, or even quite frequently a parasite, for example Giardia. The study was very enlightening and has been the basis of a hypothesis we have developed that poly-microbial infections are significant and that we really ought to be investigating and treating these appropriately.”

Cholera Virus - blood in a test tube
Credit: mrtom-uk.

Actionable Insights: Treating All of the Right Bugs

You know the story. A patient goes to the doctor for a bacterial or viral infection and is sent home with antibiotics or a prescription of rest and cough medicine. But it’s not long before that same patient is back for a serious “secondary” infection – yeast infections, a staph infection, pneumonia. We usually think of secondary infections as being caused by coming into contact with a second, new bug while our immune system was busy trying to fight off the first, such as the influenza virus. But what if these “second” bugs were there all along, but we just didn’t know it?

“What we have been calling secondary infections may in fact be infections left untreated by single antibiotic treatments, because we haven’t recognized that there is more than one pathogen present in the first place,” Rita said.

Let’s say we treat a patient showing symptoms of a particular infection with a single antibiotic, assuming that the antibiotic will kill or inhibit the single microorganism that we believe is causing the infection. Our patient begins to improve, and all seems well.

What we don’t know, however, is that the patient came to us with another microorganism in the infection that was resistant to the antibiotic we prescribed. What happens? The patient develops what we believe to be a secondary infection, which is really due to the resistant microbe gaining ground as the one we treated for has been inhibited or killed.

“If we were able to detect the presence of all of the microorganisms, especially the pathogens, present in the first place, and their resistance to given antibiotics – which we can do today – we could select a combination of antibiotics or other drugs that would treat all of the pathogens present in the infection,” Rita said. “I don’t think it’s an exaggeration to say that we have very little knowledge of how specific fungi, viruses, bacteria, and even parasites, when they are all present and interacting, which they obviously could, impact health and wellness.”

Researchers like Rita are finally getting a chance to detect, in a single “microbiome” snapshot, the mixture and complexity of microorganisms present in our gut and on the surfaces of our body, including mucus membranes, etc., that play a role in infection and disease.

Our progress in understanding infectious diseases based on microbial genome sequencing parallels our progress in understanding individual variation of various types of cancer. By sequencing cancer biopsies, for example, researchers have determined that cancers given the same general name (e.g. breast cancer, brain cancer) represent different diseases when examined individually, based on genetic signatures. We might get to the same point with treatment of infections and infectious diseases. Each patient may need to be treated according to the microbial communities in their  gut or on their skin, for example. We will also likely begin to understand better about why some individuals are at greater risk of contracting a disease because of unique susceptibility to particular pathogens, or perhaps because they lack protective microorganisms in their gut or elsewhere in or on their body.

“What I think we may find out is that those who end up in the emergency room or in the hospital with a really serious infection may actually have more than one pathogen that should be properly treated,” Rita said. “Biology being what it is, one should not say never and never say always. But very frequently, I think, we will find that serious cases may be traced to mixed infections.”

A Picture of Gut Health

I asked Rita how her research has influenced how she approaches the microbes living in her own gut and how she keeps these communities healthy.

“I find myself today not exactly a strict vegetarian but sticking to a heavy plant-based diet with some fish and chicken now and then,” Rita said. “I also eliminate as much salt and saturated fats from my diet as I can, which means that, thankfully, my cholesterol has dropped significantly to a healthy number. My physician is quite happy with that! But I think it is true what Brenda Davis, the nutritionist/dietician, postulated decades ago, that diet does play a major role in human health and in preventing diseases like cancer. We are now learning  about the relationship  between the microbiome and colon cancer, for example. Eating healthy includes selecting those foods that will enhance microorganisms in the gut that can provide better end products to be absorbed in our diet.”

When it comes to pre- and probiotics, we still have a lot to learn, Rita says. She likens the gut health supplements many of us take today to the first cell phones.

“Those cell phones were so clumsy and large that they almost needed wheels,” Rita laughs. “But today, we have cellphones that are essentially powerful computers that fit in the palm of our hand.  I think we are still in the ‘early cell phone days’ of understanding how to manipulate the communities of microorganisms in our gut. So, while eating yogurt or drinking buttermilk is a good practice for most people, probiotics provide only a very approximate and still imperfect treatment for gut health. We don’t really know how to create the perfect mix of microorganisms, nor do we know how to introduce the microorganisms effectively into the gut, to optimize health – we are getting there, but we aren’t there yet.”