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University of Delaware chemical biologist Catherine Grimes says
she and her lab are “somewhat obsessed” with fragments of bacterial cell
walls because they hold great potential for advances against disorders
of the immune system.
It has no facial
recognition software, no fingerprinting system, no ID cards to scan and
verify. But the human immune system is constantly evaluating the
identity of the bacterial cells it encounters. Are they the friendly
type — the ones that help digest food, for example? Or are these enemy
agents, likely to create trouble and misery wherever they go?
These first impressions are critical to the immune response and
scientists are eager to understand more about the processes behind that
response. With that kind of knowledge, new therapies and precise medical
approaches can be used to arrest or prevent disorders of the immune
Millions around the world suffer from chronic inflammatory disorders
caused by inadequate responses to the microbiome, the huge population of
microorganisms that share our bodies. Enhanced immune responses or
delayed healing create something like a civil war within the body,
prompting tissue damage and organ dysfunction. Inflammatory bowel
diseases such as Crohn’s Disease and ulcerative colitis are examples of
Now the labs of University of Delaware chemical biologist Catherine
Leimkuhler Grimes and immunologist Hans-Christian Reinecker of the
University of Texas Southwestern Medical Center have produced potent new
tools that offer researchers precise, new perspectives on how the
immune system is triggered and what happens in the cascade of responses
Grimes’ research has focused on just this kind of work. She and her
team of students study what happens when the human immune system first
encounters the cell walls of bacteria, whether the bacteria are
commensal (bringing benefits to the body) or pathogenic (causing
illness). To learn about those first encounters, they have studied the
outermost shell of bacterial cells by studying the bacterial
peptidoglycan (PG) fragments that bacterial cell walls are made of.
Grimes’ lab has looked at many angles of peptidoglycan. In a recent publication of the American Chemical Society’s journal Chemical Biology,
for example, her team, led by graduate student Ashley Brown, builds on
their metabolic engineering work, prompting bacteria to produce cell
walls with modified building blocks. This allows fundamental features of
these barricades to be understood. Fragments of these cell walls
eventually are sloughed off, but now they contain something like hooks
that capture physiologically relevant bits.
Grimes said she and her team are somewhat obsessed with these
fragments because they hold great potential for cancer therapies and
immune system modulation.
The fragments used in traditional immunological experiments are
muramyl dipeptides (MDP) — readily available “off-the-shelf” minimal PG
fragments that have provided much insight into innate immune responses
Grimes and her team have built on this work in collaboration with the
Reinecker lab. The teams have shown that more biologically relevant,
complex PG fragments — exactly the kind the immune system would see —
can be synthesized in the lab. They also have demonstrated that these
biologically inspired synthetic fragments reveal more complex signaling
than was previously recognized.
In this project, Grimes’ students synthesized four variations of PG
fragments to see what kind of immune responses would occur with each.
For one, they were inspired by the bacterial breakdown products found in
cultures of Lactobacillus acidophillus, a bacterium normally found in
your gut or the yogurt you eat. The team found that each of the four
derivatives had unique genetic signatures and produced unique responses,
all of them different than MDP would have produced. The product from
the human gut bacteria produced the most potent response.
Move this whole section up, swapping places with the section above it.
This selfie was taken before the COVID-19 pandemic occurred (and
necessitated masks and distancing), as Kristen DeMeester (left), Kimmie
Wodzanowski (center) and University of Delaware Professor Catherine
Grimes were working late.
Earlier this year, the researchers published their findings
in ACS Central Science, a journal of the American Chemical Society, and
now are working to develop a library of relevant PG fragments in a
project supported by a $1.9 million grant from the National Institute of
General Medical Sciences (NIGMS). The new funding will yield data that
will be critical in future development of antibiotics and treatments for
inflammatory disorders and is complementary to the funding Grimes and
her team received to metabolically engineer bacterial cell walls.
"These are the small molecules we should be using,” Grimes said. “And
if these things truly become immune modulators, they could be used in
all kinds of front-line work.”
As an example of the potential gains these new tools provide,
Reinecker said they identified more than 30 genes related to
inflammatory bowel disease that were activated in response to the gut
bacteria fragment the Grimes Lab synthesized.
“It all starts with having sufficient research tools,” he said.
“These components are now in our hands and that is critical for getting
at these pathways…. Once we have the mechanisms, we can interfere with
them. We can block them or enhance them. Now we have components that
will allow us to more precisely understand how the immune system
Grimes’ collaboration with Reinecker stems from her days as a
postdoctoral researcher at Harvard with Dr. Daniel K. Podolsky.
Reinecker was establishing his lab at Massachusetts General Hospital at
the time and the two would often talk in the hallway about the missing
tools that immunologists desperately needed.
“This is a beautiful collaboration — chemistry with immunology,” Reinecker said.
Grimes’ students produced the chemical fragments Reinecker’s
immunology lab needed for experiments that simply couldn’t be done with
the simpler “off-the-shelf” MDP probes. Reinecker’s immunology lab, in
turn, gave Grimes’ students insight into how their fundamental science
can provide powerful new possibilities for medical research.
Lead authors Kristen DeMeester and Klare Bersch both earned their
doctorates at UD during this work. DeMeester now is working at Scripps
Research in California and Bersch works as a medicinal chemist at
Prelude Therapeutics in Wilmington, Delaware.
“I’m a synthetic chemist, but I hadn’t done any biological assays
prior to this experience,” DeMeester said. “Now I do a lot of it.
Infecting cells is all I do.”
Both had key roles in this work. DeMeester helped identify the
fragments needed for the work in collaboration with Kimberly
Wodzanowski. Bersch synthesized and characterized them and established
the process for others to use in the lab so future testing can continue.
“You can’t get these from a vendor,” Bersch said. “You have to have a synthetic chemist.”
Once they had synthesized the compounds they wanted to use, they took
them to Reinecker’s lab in Boston (before he moved to Dallas) and
worked with Rachid Zagani there to treat macrophage cells (the cells
that provide immune defense), extract genetic material and test it.
They found exciting things.
“Each fragment we tested had a different signature of genes,” Bersch said. “They were unique responses.”
The immunologists in Reinecker’s lab also got new insights from the project.
“As chemists, we look at the structure of molecules, bonds and
atoms,” DeMeester said. “We’re looking at atomic networks. Immunologists
look at cells in that complex way, in those types of networks. But
they’re looking at cellular protein networks.”
Grimes said making these new molecular probes available will expand
the capacity of researchers to pursue new questions and will surely lead
to new findings.
Having just one primary kind of probe restricted the insight researchers could gain.
Grimes said it reminded her of her daughter’s fondness for the color
pink. It is her “go-to color” in the crayon box. Everything winds up
“Just as I’m trying to teach my daughter that there is more than one
color in the box to choose and how much more could be represented on the
paper with all of the colors, Christian and I are trying to teach the
immunologists that there is more than one peptidoglycan fragment and
it’s important to use more than one,” Grimes said. “We need to widen our
palette when considering the depth of immunological response around
DeMeester said it is exciting to be part of such work.
“This really shows the power of collaboration and how great it can
be,” DeMeester said. “The best part of the whole thing for me was seeing
something for the first time that the world hasn’t seen before. I
wouldn’t be the scientist I am without my mentor Catherine Grimes.”
Also participating in the collaborative research were Siavash
Mashayekh and Kimmie Wodzanowski of UD’s Department of Chemistry and
Biochemistry and Shuyuan Chen and Shuzhen Liu, both of the University of
Texas Southwestern Medical Center.
The work was supported by the Delaware COBRE (Centers of Biomedical
Research Excellence) Program with a grant from the National Institute of
General Medical Sciences, by the National Science Foundation and by
grants from the National Institutes of Health.
Catherine Grimes is professor of chemistry and biochemistry at the University of Delaware and co-director of the Chemical-Biology Interface
Graduate Program at UD. She earned her bachelor’s degree in chemistry
at Villanova University, her master’s at Princeton University and her
doctorate at Harvard University, then did a postdoctoral research
fellowship at Harvard and Massachusetts General Hospital before joining
the UD faculty in 2011. She has been recognized with many awards and
honors and has been named an Alfred P. Sloan Research Fellow and a Pew
Biomedical Scholar. She was recently selected for the David Gin Young
Investigator Award by the American Chemical Society. She is most proud
of the students that she mentors through her research and teaching.
Article by Beth Miller;
Photo illustration by Jeffrey C. Chase; Photos by Evan Krape and courtesy of Catherine Grimes
Published December 02, 2021