Stories about: Min Dong

Science Seen: An intestinal toxin’s trick, a potential cancer fighter

Crystal structure of the C. difficile toxin bound to its receptor, causing intestinal damage
Adapted from Science May 11, 2018. DOI: 10.1126/science.aar1999

Clostridium difficile, also called “C. diff,” causes severe gastrointestinal tract infections and tops the CDC’s list of urgent drug-resistant threats. In work published in Nature in 2016, Min Dong, PhD, and colleagues found the elusive portal that enables a key C. diff toxin, toxin B, to enter the intestines’ outer cells and break down the intestinal barrier (above right).

Interestingly, the same portal, known as the Frizzled receptor, also receives signals that maintain the intestine’s stem cells. When toxin B docks, it blocks these signals, carried by a molecule known as Wnt. But exactly how it all works remained a puzzle — until new research published today in Science.

Liang Tao, PhD in Dong’s lab, working with the labs of Rongsheng Jin, PhD, at UC-Irvine, and Xi He, PhD, at Boston Children’s, captured the crystal structure of a fragment of toxin B (in orange above) as it joined to the Frizzled receptor (in green). The structure revealed lipid molecules within the Frizzled receptor (in yellow and red) that play a central role. Normally, when Wnt binds to Frizzled, it nudges these lipids aside. But the team showed that when the toxin fragment binds to Frizzled, it locks these lipids in place, preventing Wnt from engaging with the cell.

Just as stem cells rely on Wnt signaling for growth and regeneration, so do many cancers. Now that its mechanism is known, Dong thinks this toxin B fragment, which by itself isn’t toxic, could be a useful anti-cancer therapeutic. They’re currently developing a new generation of Wnt signaling modulators and testing them in animal models of cancer. (For further information, contact Rajinder.Khunkun@childrens.harvard.edu of Boston Children’s Technology & Innovation Development Office.)

Read Full Story | Leave a Comment

Botulinum-type toxins jump to a new kind of bacteria. Should we sound an alarm?

(Illustration: Elena Hartley)

Enterococci are hardy microbes that thrive in the gastrointestinal tracts of nearly all land animals, including our own, and generally cause no harm. But their ruggedness has lately made them leading causes of multi-drug-resistant infections, especially in settings like hospitals where antibiotic use disrupts the natural balance of intestinal microbes.

So the discovery of a new toxin in a strain of Enterococcus is raising scientific eyebrows. Isolated from cow feces sampled at a South Carolina farm, the bug was unexpectedly found to carry a toxin resembling the toxin that causes botulism. The finding was reported this week in the journal Cell Host and Microbe.

“This is the first time a botulinum neurotoxin has been found outside of Clostridium botulinum — and not just the toxin, but an entire unit containing the toxin and associated proteins that prevent the toxin from being degraded in the GI tract,” says Min Dong, PhD, a scientist in Boston Children’s Hospital’s Department of Urology and Harvard Medical School and one of the world’s experts on botulinum toxins.

Read Full Story | Leave a Comment

Botulism toxin X: Time to update the textbooks, thanks to genomic sequencing

botulinum toxin X
Botulinum toxin X is the first new botulinum toxin to be identified since 1969. (Jason Wilson/Flickr)

Botulism is a rare, potentially fatal paralyzing illness. It’s the reason we shouldn’t feed infants honey and why we need to take care in consuming home-canned foods: they can potentially contain nerve-damaging toxins produced by Clostridium botulinum. Botulinum toxin is classified as one of the six most dangerous potential bioterrorism agents.

There are seven known types of botulinum toxin. Toxins A and B were first identified in 1919, and first purified in 1946 and 1947, respectively. (Both are also used medically.) Toxins C, D, E and F eventually followed. The last, toxin G, was identified in 1969 in soil bacteria in Argentina.

And that’s where it’s stood until now. But to truly defend against botulism, we need to know all the toxins made by the various C. botulinum strains, since each requires a separate antibody to neutralize it.

Read Full Story | Leave a Comment

Mutated botulinum neurotoxin B: A stronger player in the Botox world?

Clostridium botulinum

Famously associated with smoothing out wrinkles, botulinum toxin — better known as Botox — has been in use for 40 years now. Initially approved as a treatment for crossed eyes and then facial wrinkles, its on- and off-label uses today extend to urinary incontinence, migraines, perspiration, spasticity and even depression. But the diffusion of the toxin away from the injection site can also cause side effects like difficulty swallowing and drooping of the face.

Now, scientists have created an altered botulinum toxin, one that works much better than its natural version and with potentially fewer side effects. Their findings are written up in Nature Communications.

Read Full Story | Leave a Comment

Entry door for deadly C. difficile toxin suggests new mode of protection

Clostridium difficile
C. difficile (Wikimedia Commons)

Clostridium difficile, also called “C. diff,” tops the CDC’s list of urgent drug-resistant threats. Marked by severe diarrhea and intestinal inflammation, C. diff has become a leading cause of death from gastrointestinal illness, causing half a million infections a year in the U.S. alone.

C. diff flourishes best in hospitals and long-term care facilities where people are on long-term antibiotic treatment. “Antibiotics clear out the normal intestinal bacteria and create a space for C. diff to colonize and grow in the colon,” says Min Dong, PhD, who researches bacterial toxins in the Department of Urology at Boston Children’s Hospital.

In today’s Nature, Dong and postdoctoral fellow Liang Tao, PhD, together with researchers at University of Massachusetts Medical School, reveal how C. diff’s most potent toxin gets into cells. The toxin’s entryway, a receptor called Frizzled, provides an important and interesting clue to fighting the hard-to-eradicate infection.

Read Full Story | Leave a Comment