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Terminalia
Chebula in cystic fibrosis
Terminalia Chebula in Cystic Fibrosis
Achievement of Young Scientist of
Indian Origin
by
Amy Hodson Thompson
Cogito,
12.12.2006
It’s not what you know; it’s who you know, right? Well…in
science, not quite. For seventeen-year-old Madhavi Pulakat Gavini,
it was the “what” - her new potential treatment for Pseudomonas
infection - that won her 2nd place at the Siemens National
Competition and a $50,000 college scholarship to add to her 2006
Intel International Science and Engineering Fair grand prize win.
For Madhavi, “who” is an important factor, but in a different way.
Pseudomonas aeruginosa (P. aeruginosa), a bacterium
that is common in water, soil and on plants, causes serious or
deadly infections in people who are immune compromised. A friend’s
aunt, who Madhavi came to know well, had cystic fibrosis (CF). For
CF patients, Pseudomonas infection of the lungs is one of their
number one killers. “So I looked up everything I could about CF
when she told me about it,” says Madhavi. “My project just took
off from there.”
Plants vs. Bacteria
Madhavi’s grandfather, an Ayurveda traditional
medicine practitioner and physician in India, encouraged her to
test Ayurveda’s traditional herbal extract treatments against P.
aurigenosa. She selected 10 extracts used to treat lung
conditions. “I just grew my P. aeruginosa strain on the plates and
spotted the extracts onto the plates also to see if any of them
could inhibit bacterial growth,” says Madhavi. “A couple had a
pretty small zone of inhibition, but one particular extract,
Terminalia chebula (Tc), dramatically inhibited the bacteria’s
growth.”
“Millions of people suffer from chronic
Pseudomonas infections,” says Madhavi. “An antiseptic spray or
inhaler could greatly improve their quality of life as well as
increase their lifespan.”
Madhavi thought she might have something important, but knew
she needed to put aside her extracts for a while. P. aeruginosa,
because it can live in and infect such a wide variety of
organisms, from plants to humans, has different forms. The “rough”
form, named for its appearance on a bacterial plate, is a common
strain found in soil, water, and plants. This is the laboratory
strain Madhavi used in her initial experiments. But in humans, P.
aeruginosa is usually in a “smooth” form, a strain that grows an
additional, sticky polysaccharide coat, and often exists in a
complex bacterial community called a biofilm. Biofilm-forming
strains, with their ability to stick to lung cells and resistance
to antibiotics, pose the biggest threat to humans. Madhavi needed
to test her extract on a biofilm variant.
Up to this point, Madhavi had been pursuing her project for fun
over the summer before her junior year of high school in the
biology lab of Dr. Lakshmi Pulakat, her mother and mentor at
Mississippi State University. When she started at the Mississippi
School for Mathematics and Science (MSMS), she took the project
with her. It was Madhavi’s first year at the boarding school, and
she was really enjoying the atmosphere. “There are students here
who are definitely interested in research, and a lot of them are
pretty gifted. So it’s fun,” says Madhavi.
Madhavi enrolled in MSMS’s dual research program that took her
to MSU for research during the week, and she worked on weekends
and over school breaks too. She had plenty of resources, but she
didn’t have one essential piece for her next step – isolating a
biofilm-forming Pseudomonas. “I read in a couple of different
places that in order to get it to grow biofilm you need what’s
called a drip column,” says Madhavi. “It’s rather expensive so I
just wanted to see if I could come up with another way of
manipulating the bacteria so it will grow the biofilm.”
Engineering this new technique became her independent study
project in microbiology class.
Fishing for a Biofilm
Pseudomonas’s biofilm has two main functions:
the first is protection, and the second is to allow the bacterium
to adhere to smooth surfaces like the epithelial cells in our
lungs. The biofilm’s stickiness also makes the cells adhere to
plastic. So Madhavi put plastic micropipette tips in cultures of
bacteria floating in water and growth medium. The stickier biofilm-forming
bacteria grew on the tips, and this allowed Madhavi to “fish” out
few biofilm-forming chromoisolates from the “rough” strain.
Now it was time to test Tc against biofilm-forming P.
aeruginosa. When Madhavi looked at the large zone of inhibition
produced by Tc against her new isolate, she knew that she was
looking at something big. None of the drugs for Pseudomonas
infection currently on the market could do what Madhavi had just
accomplished: inhibit both rough and biofilm-forming P. aeruginosa.
Madhavi’s grandfather never got to hear about Tc’s success, he
died in the spring of 2005. But she still had another influential
“who” to consult in India, her physician and Ayurveda practitioner
grandmother. “She would go back and talk to my mother about her
project,” says Dr. Pulakat. “She wanted to confirm the fact that
Tc was not dangerous.” Madhavi’s grandmother reassured her that
the extract has been used as a medicine for thousands of years,
and is even safe enough to give to infants. Madhavi, hoping to
turn Tc into an effective treatment for P. aeruginosa, set about
trying to determine exactly what molecule in the extract was
responsible for its action.
Unmasking a Molecule
Madhavi painstakingly determined that Tc
retained effectiveness even after 100-fold dilution, after having
been sterilized with the extreme heat and pressure of an
autoclave, and after passing through a 0.1 micron filter. Then,
because all her experiments had tested Tc against new bacterial
growth, she pitted it against bacteria that had already been
growing for 5 hours. Within 2 hours of Tc treatment, the P.
aeruginosa was dead. Tc’s ability to kill bacteria even through a
biofilm was confirmed.
Read more about Madhavi in the
January/February Medicine and Health Sciences issue of
Imagine Magazine, JHU/CTY's magazine for gifted students.
Genetic analysis was next. Madhavi exposed growing cells to Tc,
harvested their RNA and compared it to untreated control cell RNA
using microarray analysis. When Madhavi finished analyzing the
nearly 6,000 microscopic bright gene spots on her chips to
determine the levels of RNA for each protein in treated and
untreated cells, the reason behind Tc’s effectiveness was clear.
Tc-treated bacteria had a reduction in expression of genes
necessary for biofilm production, for energy metabolism, and for
infecting cells.
Now, Madhavi is working towards developing an inhaler to
deliver Tc to the lungs or a spray to deliver Tc to the skin,
surfaces, or environment as a way to prevent infection. “I
envision Tc extract being used in a multitude of everyday products
ranging from household cleaning supplies, to contact lens
solutions to toothpaste additive,” said Madhavi in the conclusion
to her Siemens competition presentation. She has proved that
linking the extract with gold nanoparticles so that they can be
tracked in living animals does not compromise its action, and her
next step is to test the extract in a mouse cystic fibrosis model.
“Millions of people suffer from chronic Pseudomonas infections,”
says Madhavi. “Such an antiseptic spray or inhaler could greatly
improve their quality of life as well as increase their lifespan.”
If Tc’s promise holds, who knows how many “whos” Madhavi may
end up helping.
Madhavi
Pulakat Gavini is a senior at the Mississippi School for
Mathematics and Science. She enjoys late-night hot chocolate
parties in her dorm, has lots of plants, and is a voracious
reader. She was a National History Day finalist in 2005 with a
paper about Linus Pauling and his stance on nuclear weapons. She
intends to pursue biomedical research as a career.
Courtesy : Cogito.Org
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