|Katharina Ribbeck has heard every phlegm, booger, and loogie joke in the book. But her research on mucus reveals it to be a marvel of engineering – and a critical line of defense in the immune system. Photo, Buck Squibb.|
Snot. Boogers. Phlegm. The goo that drips from your nose when you have a cold. No matter what you call it, mucus has a bad reputation as an unpleasant waste product, a sign of disease.
But despite its high ick factor, the slimy substance performs a remarkable range of vital functions. After all, it lines more than 200 square meters of our bodies – from our mouths to the digestive system, urinary tract, lungs, eyes, and cervix. It lubricates and hydrates, lets us swallow, determines what we taste and smell, and selectively filters nutrients, toxins, and living cells such as bacteria, sperm cells, and fungi. “It’s a really amazing barrier,” says Katharina Ribbeck, an associate professor of biological engineering. “It allows us to integrate nutrients; it protects us from pathogens. It’s also a major obstacle to drug delivery. But we have no idea how it works.”
Ribbeck and her students are out to change that. By studying this sticky hydrogel, she hopes to devise new ways to diagnose and treat human disease. “There is a lot of information about our health in mucus,” she says. “Our goal for the next couple of years is to tap into this underutilized source of bioinformation and use it.”
A champion for mucus
Ribbeck didn’t initially intend to focus her research on mucus. At the University of Heidelberg in Germany, she studied biology and biochemistry, and for her senior year she went to the University of California at San Diego to work on her diploma thesis in neurobiology. When she returned to Heidelberg for grad school, she began studying the biology of the nuclear pore – a channel that regulates communication between a cell’s nucleus and the rest of the cell.
Mucus, she says, “was never on my radar in grad school.” But like mucus, nuclear pores also act as selective barriers: they allow some particles to pass through while blocking others.
After finishing her PhD, Ribbeck planned to start a research group in Germany, continuing her studies of the nuclear pore. But then a friend at Harvard Medical School suggested that she spend a year working in his lab. “It’s the things you don’t do that you regret,” she says. “So I decided to go there, anticipating an interesting but not really life-changing year.”
While spending 2007 as a visiting scientist there, Ribbeck heard about a Harvard fellowship that would provide a lab, startup funding, and status as an independent investigator. The catch? Applicants had to propose starting a new field of study.
Mucus was not well studied then, but it was known to play a key role in maintaining health. Ribbeck made a case for starting a mucus lab – and got the fellowship.
Early during her time at Harvard, she realized that the study of mucus would benefit from the expertise and tools being developed in MIT’s Department of Biological Engineering – in tissue science and engineering, microfluidics, and more. She joined the faculty in 2010, earning tenure in 2017.
“I was immediately impressed by the vigorous spark of creativity Katharina expressed,” says Douglas Lauffenburger, the department’s head. “The topic of her research interests at first seemed rather peculiar, but her articulation of its broad importance in microbiology and medicine, and of her goal to understand it fundamentally in ways that could lead to design of valuable technologies, was deeply compelling.”
Fending off infection
Among the phenomena Ribbeck has investigated is that mucus is very successful at “taming” normally pathogenic microbes. Until recently, scientists thought this was simply because it acted as a mechanical barrier, trapping bacteria and other pathogens. However, Ribbeck’s work has shown that mucus plays a much more nuanced role.
The primary building blocks of mucus are mucins – long, bottlebrush-like proteins with many sugar molecules called glycans attached. And mucins, Ribbeck discovered, actually disrupt many key functions of infectious bacteria. “In the presence of mucins, the traits that make these pathogens virulent are significantly downregulated,” she says. “That includes secretion of toxins, the ability to chitchat with each other, and the ability to attach to cellular surfaces.”
With those powers cut off, bacteria can no longer colonize on a surface to form persistent slimy layers called biofilms, which tend to be more harmful than the cells are individually: they can cause a wide range of health problems, including dental cavities and ulcers, and can prove fatal for people with cystic fibrosis.
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Ribbeck’s lab figured this out by purifying mucus from a pig stomach to isolate a mucin called MUC5AC, which is related to one found in the human respiratory tract and stomach. The researchers then created three-dimensional matrices with and without the mucin and inserted infectious bacteria called P. aeruginosa in both. The bacteria in the matrix without MUC5AC attached to the surface of the matrix, forming dense biofilms. In the MUC5AC matrix, no biofilms formed. But when the researchers deleted a gene in the bacteria that allowed them to keep moving, they found something interesting: the infectious bacteria in the MUC5AC matrix did clump together, mimicking the material that builds up to produce abnormally thick mucus in cystic fibrosis. What that meant, Ribbeck found, was that while mucin does trap things like dust and other inhaled particles, in the case of the bacteria it does the opposite, keeping them moving so they can’t form biofilms. Her group found the same was true with other kinds of microbes, including Candida.
Ribbeck’s research also revealed that glycans – the complex sugar molecules in mucin – are the key to its ability to foil pathogens. It had been assumed that their primary role was to make mucin polymers stiff, and her lab and others had isolated glycans in order to count how many distinct types there were. Mucins, it turns out, contain hundreds of different glycans. But beyond counting them, Ribbeck also compared the glycans in mucin in different parts of the body – and began investigating what they actually do. By comparing natural mucins with mucins that had their glycans removed, she discovered that these sugars are essential to mucins’ ability to repel bacteria and prevent them from attaching to surfaces. Initially surprised by this finding, she realized that glycans in human milk perform a similar function, helping babies stay healthy by serving as soluble receptors that essentially distract ingested pathogens, preventing them from adhering where they could cause infection. In a way, she says, mucus is “like breast milk for adults.”
Ribbeck is now investigating the specific functions of the hundreds of glycans that have evolved to interact with and disable different pathogens in a variety of ways. She thinks of mucins as containing a vast library of different molecules that stand ready to be checked out to engage whatever microbes happen by, whether they are viruses, bacteria, fungi, or parasites. “Imagine how beautiful that is,” she says.
Engineers have long been interested in designing materials that mimic mucus, largely for its lubrication abilities. However, the intriguing antimicrobial traits that Ribbeck’s lab has uncovered have led many researchers to begin working on synthetic versions of mucins for possible use in treating or preventing infectious disease. Some preliminary studies from Ribbeck’s lab suggest that mucins can effectively treat wounds infected with bacteria that are resistant to traditional antibiotics.
A diagnostic tool
Ribbeck’s lab is also analyzing how stickiness and other biophysical properties of mucus change during illness, which could help researchers discover biomarkers that could be used to diagnose many different diseases. In recent years, she has published studies showing that changes in the cervical mucus of pregnant women can reveal their risk of going into labor too early.
More than 10 percent of babies born worldwide arrive before full term, defined as 37 weeks of gestation, but there had been no reliable way to predict preterm labor. In hopes of coming up with a useful predictor, Ribbeck analyzed the chemical and mechanical properties of cervical mucus. She’s found that the mucus from women at high risk of early labor is mechanically weaker, more elastic, more permeable, and less adhesive. Preterm birth may occur because the cervical mucus is more susceptible to invasion by microbes that can cause infection.
Other conditions that alter mucus include digestive diseases such as Crohn’s and ulcerative colitis, as well as respiratory diseases. The “holy grail” of diagnostics, Ribbeck says, is to link changes in saliva composition with diseases that affect mucosal surfaces throughout the body.
“If you have aberrant mucus production in your mouth, there is a chance that this is true for other parts of the body,” she says. “So we might be able to pick up, from saliva, disease conditions of remote mucosal surfaces. That will be very exciting, because of course that is noninvasive yet informative.”
Ribbeck says that her research is a natural topic of interest for children, which she takes advantage of to get them excited about science. At “Grossology” summer sessions offered at Boston’s Museum of Science, she and her students teach elementary and middle school students how to make polymer networks, using slime as their material of choice. The children also learn about mucus’s unique barrier properties and why it feels so slimy.
“The intention here is to really introduce a field to the generations to come, so they grow up understanding that mucus is not a waste product. It’s an integral part of our physiology and a really important piece of our health,” she says.
She is also working on a children’s book starring a shape-shifting character made of mucus, highlighting the many roles that it plays in our bodies.
“Kids are really fascinated by mucus, and I think part of that fascination might not go away for adults,” Ribbeck says. “The other thing that makes it intriguing to so many people, including myself, is an element of surprise when you find such exquisite and elegant pieces of engineering in something as common as mucus.”
– Anne Trafton, MIT Technology Review
December 19, 2018