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Margaret McFall-Ngai Sees Benefits of Relationships Between Microbes and Humans

Bacteria, fungi, yeasts, viruses, amoebas - trillions of them naturally take up residence in and on human beings. We usually think about them only when they make us sick, or threaten to. Now it appears that microorganisms play a much more important role than ever suspected in keeping us healthy - indeed, alive.


That may be the ultimate lesson learned from the recently completed Human Microbiome Project (HMP), a five-year, $153 million National Institutes of Health (NIH) initiative that brought together more than 200 scientists from some 80 research centers to start taking a census, of sorts - a tally to identify the microbiome, the complete collection of all the microorganisms that typically live in and on the human body.


Margaret McFall-Ngai has used the tiny Hawaiian bobtail squid (seen here with its reflection) and its bacterium partner to understand broad aspects of symbiosis and other beneficial relationships.Using samples taken from multiple spots on the skin and in the mouth, gastrointestinal tract and female reproductive tract of 242 healthy U.S. volunteers, researchers sequenced the RNA and DNA of the microorganisms they found and used super-computers to analyze the genetic data.


"The scientists were stunned by what they learned," says Margaret McFall-Ngai, PhD, professor of medical microbiology and immunology at the University of Wisconsin School of Medicine and Public Health (SMPH) and a member of the Symbiosis Cluster at UW-Madison. "The number and complexity of microorganisms was well beyond what they expected."


But McFall-Ngai has never doubted the importance of the relationships between microbes and humans.


An expert on symbiosis - the state in which two different organisms from separate species co-exist - she studies the partnership between the tiny Hawaiian bobtail squid and the luminous bacterium called Vibrio fischeri that lives inside it. She has found it to be an ideal system for exploring broad issues about how disparate organisms cooperate in fundamental ways to survive. A thought leader held in high esteem by the microbiome community, she was invited to attend nearly every HMP meeting convened.


The new studies revealed that more than 100 trillion microorganisms - some of them never seen before - live peacefully in or on each of us. The microorganisms are organized into thousands of different types, a much greater degree of diversity than previously imagined, and many gather at specific body sites - under the gums, in the colon, on the hand and up the nose.


The microbes connect to epithelial tissues, the cellular coverings of internal and external body surfaces; these interfaces have intrigued McFall-Ngai since the beginning of her career.


Each microorganism contains thousands of individual genes that actively contribute to many vital functions, including helping with digestion by breaking down starches, producing anti-inflammatory substances, synthesizing vitamins, promoting the storage of energy from fat, and priming the development of newborn immune systems.


From the Human Microbiome Project analysis, scientists conclude that each person has a distinguishing microbial signature; stool samples showed, for example, that no two people had the same combination of microorganisms living in their gut. But across the study population, many similarities were seen.


"Cities offer a good analogy," says McFall-Ngai, a comparative animal biologist by training. "San Francisco is uniquely San Francisco due to all its own characteristics. Yet there are groups of people living there - bakers, sanitation workers, police officers - that are common to almost all cities."


While almost everyone harbors species that have the potential to be harmful - such as Clostridium diffiicile, Staphylococcus, Candida, E. coli and Helicobacter pylori - these microbes live in harmony with humans most of the time. But illness, stress or the use of antibiotics can throw off the normal balance, allowing some microorganisms to overgrow and cause damage.


"If the police force in the microorganism community is greatly reduced, robbers who are usually law-abiding may now take advantage," says McFall-Ngai, extending the city analogy.


Eventually, the human microbiome returns to a state of equilibrium, although possibly not in exactly the same way as before.


McFall-Ngai was excited to learn from the Human Microbiome Project results that microbes appear to have been with humans since humans began evolving, a theory supporting the idea that microorganisms are essential to human existence. It’s a theory she has trumpeted for a long time, often on deaf ears.


"The most dramatic HMP outcome, one that really confirms the value of microbes to my mind, is that microbial molecules found in blood, sweat and urine contribute 36 percent to the makeup of the human metabolome, the full complement of metabolites present in humans," she says. "This shows that even when microbes are not present in a particular site in the human body, the products of their activity can affect those sites."


Insights from Squid–Vibrio


Studies in the relatively simple squid–Vibrio system have helped McFall-Ngai and her collaborator Ned Ruby understand important issues such as how bacteria influence animal development.As the Human Microbiome Project researchers concluded their studies this summer, McFall-Ngai completed a John Simon Guggenheim fellowship that included a sabbatical year in which she was the Gordon and Betty Moore Professor at the California Institute of Technology (Cal Tech). The fellowship allowed her to continue thinking expansively about her work and its implications.

For 24 years, she has evaluated the value of persistent, mutually beneficial relationships between different species as she has studied the bobtail squid and its partner the Vibrio. The more she's learned from this relatively simple model system, the more she’s extrapolated to the bigger picture.


The luminescent Vibrio helps the nocturnal squid produce light during its nighttime searches for food, allowing the squid to escape from fish predators.


"With the help of the Vibrio, the squid emit ventral luminescence that is often very, very close to the quality of light coming from the moon and stars at night," explains McFall-Ngai. To hungry fish peering up from below, the squid appear camouflaged against the moon or the starlight because they don’t cast a shadow. The squid expel most of the Vibrio population each dawn, nurturing a new batch during the following day.


McFall-Ngai first became interested in squid–Vibrio symbiosis when she was a graduate student at University of California-Los Angeles. She convinced microbiologist Ned Ruby, PhD, then at the University of Southern California, to examine the bacterium–fish partnership with her. At the time, it was the only experimental symbiotic system in which neither partner would be harmed if the other were removed.


McFall-Ngai and Ruby, a School of Medicine and Public Health professor of medical microbiology and immunology, have finely tuned the model over the years. The scientists have used it to understand important aspects of symbiosis: the signaling that occurs between partners as symbiosis is established and maintained, how balance is maintained between the partners, the influence bacteria have on animal development, differences and similarities that exist between good and bad animal–bacterial interactions, and how those interactions have evolved over time.


The work is covered widely in the media, and the researchers are invited often to speak about it.


One key finding, which earned a place on the cover of Science in 2004, involved two molecules - lipopolysaccaride, which sits on the surface of Vibrio and all other gram-negative bacteria, and peptidoglycan, which comprises the next layer down on the cell wall. The molecules typically work together to trigger immune responses such as inflammation. But McFall-Ngai and her team discovered that the Vibrio also uses them to induce development in the squid tissues with which it will associate.


"Other scientists found, to their surprise, that the same two molecules on the surface of other bacteria were required for the development of the mouse gut," says McFall-Ngai. "We pointed the community toward molecules whose action might be conserved over evolutionary history."


Another article, published two years ago in the Proceedings of the National Academy of Sciences, showed that the persistent maintenance of the squid–Vibrio symbiosis is tied to a dynamic 24-hour rhythm that involves both partners.


"The study suggests that researchers should look for evidence of circadian rhythm in the microbiota of the mammalian gut," McFall-Ngai says. "These rhythms may play a role in normal tissue development, efficient nutrition and disease resistance."


In a "concept" article published in Nature in 2007, McFall-Ngai caused a stir among many scientists, particularly those who study immunology, with her long-held theory regarding what she sees as the main function of the adaptive immune system that is peculiar to vertebrates, including humans.


This memory-based immune system responds to each fresh encounter with the microbial world on the basis of past interactions. But invertebrates have functioned very successfully without this form of immunity. Why, then, do vertebrates need it, she asks?


"I think the adaptive immune system evolved in vertebrates not only to mount defenses against microorganisms but because of their need to recognize and manage the many complex communities of beneficial microbes that live with them," she says. "Invertebrates associate with far fewer microorganisms, so they don’t need to worry about this."


McFall-Ngai won her Guggenheim to study the immunity issue further. But she changed her goals once it became clear that the theory was gaining traction, especially among immunologists, over the past five years or so.


She used the fellowship instead to travel to several countries in Europe, where she gave talks, met scientists and learned if they were beginning to appreciate that microbiota are important for human health.


"It turns out that European scientists are more accepting of these concepts than American scientists are," she says.


Returning from Europe, McFall-Ngai gathered a group of 25 high-powered life scientists from around the globe to draft a manifesto on how microbiota may have influenced primal issues such as the origin of animals, their ecology, genomic signatures and development. The article, called "Animals in the Bacterial World: An Imperative for the Life Sciences," should be published soon.


For the final part of her Guggenheim, McFall-Ngai spent time developing, with Howard Hughes Medical Investigator Diane Newman, PhD, professor in the biology division at Cal Tech, a novel introductory biology course in which microbes were used as the unifying principle.


"Diane lectured 45 minutes on microbes, and then I followed by describing what happens when you become a multi-cellular organism," she explains. "It was a huge adventure, and I hope I can continue to develop that course."


Next Steps


The Human Microbiome Project has thrown open the door to a barrage of scientific questions and opportunities for many scientists, says McFall-Ngai, who as chair of the annual meeting of the American Society of Microbiology organized a special late-breaking plenary session on the HMP.


"Knowing which sorts of microbes normally function in healthy people can help us study the roles they play during changes in disease," she says.


Researchers are wondering, for example, how it is that H. pylori, which causes ulcers and stomach cancer, can also apparently protect against asthma. Can the microbiota found predominantly in lean people be transferred to obese people to help them lose weight? What role will probiotics really play in maintaining a healthy gut microbiome? And which microbes influence brain development?


The NIH has funded many additional medical studies building on HMP findings. And McFall-Ngai expects more.


"It is finally crystal clear that micro-organisms contribute critically to human health and survival," she says.

By Dian Land
This article appears in the summer 2012 issue of Quarterly.


Date Published: 08/22/2012

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Margaret McFall-Ngai Sees Benefits of Relationships Between Microbes and Humans

Last updated: 12/10/2012
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