Sangeeta Bhatia - Diagnosing cancer with help from bacteria
Engineered probiotics can detect tumors in the liver.
Anne Trafton | MIT News Office
May 27, 2015
at MIT and the University of California at San Diego (UCSD) have
devised a new way to detect cancer that has spread to the liver, by
enlisting help from probiotics — beneficial bacteria similar to those
found in yogurt.
Many types of cancer, including colon and pancreatic, tend to
metastasize to the liver. The earlier doctors can find these tumors, the
more likely that they can successfully treat them.
“There are interventions, like local surgery or local ablation, that
physicians can perform if the spread of disease in the liver is
confined, and because the liver can regenerate, these interventions are
tolerated. New data are showing that those patients may have a higher
survival rate, so there’s a particular need for detecting early
metastasis in the liver,” says Sangeeta Bhatia, the John and Dorothy
Wilson Professor of Health Sciences and Electrical Engineering and
Computer Science at MIT.
Using a harmless strain of E. coli that colonizes the liver, the
researchers programmed the bacteria to produce a luminescent signal that
can be detected with a simple urine test. Bhatia and Jeff Hasty, a
professor of biology at UCSD, are the senior authors of a paper
describing the new approach this week in the journal Science Translational Medicine. Lead authors are MIT postdoc Tal Danino and UCSD postdoc Arthur Prindle.
Previous studies had shown that bacteria can penetrate and grow in
the tumor microenvironment, where there are lots of nutrients and the
body’s immune system is compromised. Because of this, scientists have
been trying for many years to develop bacteria as a possible vehicle for
The MIT and UCSD researchers began exploring this idea a few years
ago, but soon expanded their efforts to include the concept of creating a
To turn bacteria into diagnostic devices, the researchers engineered
the cells to express the gene for a naturally occurring enzyme called
lacZ that cleaves lactose into glucose and galactose. In this case, lacZ
acts on a molecule injected into the mice, consisting of galactose
linked to luciferin, a luminescent protein naturally produced by
fireflies. Luciferin is cleaved from galactose and excreted in the
urine, where it can easily be detected using a common laboratory test.
At first, the researchers were interested in developing these
bacteria for injection into patients, but then decided to investigate
the possibility of delivering the bacteria orally, just like the
probiotic bacteria found in yogurt. To achieve that, they integrated
their diagnostic circuits into a harmless strain of E. coli called
Nissle 1917, which is marketed as a promoter of gastrointestinal health.
In tests with mice, the researchers found that orally delivered
bacteria do not accumulate in tumors all over the body, but they do
predictably zero in on liver tumors because the hepatic portal vein
carries them from the digestive tract to the liver.
“We realized that if we gave a probiotic, we weren’t going to be able
to get bacteria concentrations high enough to colonize the tumors all
over the body, but we hypothesized that if we had tumors in the liver
they would get the highest dose from an oral delivery,” says Bhatia, who
is a member of MIT’s Koch Institute for Integrative Cancer Research and
Institute for Medical Engineering and Science.
This allowed the team to develop a diagnostic specialized for liver
tumors. In tests in mice with colon cancer that has spread to the liver,
the probiotic bacteria colonized nearly 90 percent of the metastatic
In the mouse experiments, animals that were given the engineered bacteria did not exhibit any harmful side effects.
More sensitive detection
The researchers focused on the liver not only because it is a natural
target for these bacteria, but also because the liver is hard to image
with conventional imaging techniques like CT scanning or magnetic
resonance imaging (MRI), making it difficult to diagnose metastatic
With the new system, the researchers can detect liver tumors larger
than about one cubic millimeter, offering more sensitivity than existing
imaging methods. This kind of diagnostic could be most useful for
monitoring patients after they have had a colon tumor removed because
they are at risk for recurrence in the liver, Bhatia says.
Andrea Califano, a professor of biological sciences at Columbia
University, says the study is “seminal and thought-provoking in terms of
clearing a new path for investigating what can be done for early
detection of cancer,” adding that the therapeutic possibilities are also
“These bacteria could be engineered to cause genetic disruption of
cancer cell function, deliver drugs, or reactivate the immune system,”
says Califano, who was not involved in the research.
The MIT team is now pursuing the idea of using probiotic bacteria to treat cancer, as well as for diagnosing it.
The research was funded by the Ludwig Center for Molecular Oncology
at MIT, a Prof. Amar G. Bose Research Grant, the National Institutes of
Health through the San Diego Center for Systems Biology, and the Koch
Institute Support Grant from the National Cancer Institute.