Stanford undergrads work to create bacteria that would detect and treat intestinal diseases like an internal mini-doctor

Imagine a tiny organism that lives inside your body, detecting imbalances caused by disease and immediately responding with natural chemicals. Stanford students are attempting to engineer just such non-pathogenic bacteria, tiny agents that could detect and treat inflammatory bowel diseases by regulating cells that trigger inflammation.

If the students are successful, doctors might be able to prescribe living organisms for intestinal illnesses such as Crohn's disease and ulcerative colitis.

The group of 10 undergraduate students and their advisors form the first Stanford team to enter a bacteria "machine" in the iGEM competition, an annual contest of "international genetically engineered machines" hosted by the Massachusetts Institute of Technology. Biologists call a living bacterium a "machine" because its genes are altered from their natural state.

Engineering bacteria is but one application of synthetic biology, an emerging multidisciplinary field of creating genes that perform more functions and operate more efficiently than natural DNA. Synthetic biology involves tweaking the sequence of chemical reactions in a living cell to produce a range of medical and non-medical results, such as bacteria that release biofuel or change color to indicate temperature.

At the iGEM jamboree Oct. 30-Nov. 2, more than 120 undergraduate teams will present their own version of biological "machines" they've built from standardized, interchangeable genes called BioBricks, sent in a kit from MIT's Registry of Standard Biological Parts.

BioBricks are non-infectious E. coli genes that encode basic biological functions and have standard edges that are easily combined. Teams of students develop their own combination of genes and "stack" them on each other like interlocking building blocks to form a ring of DNA called a plasmid. Plasmids are then combined until the bacterium has all the components to produce the desired effect.

The idea for a Stanford team started last summer when co-directors Nghi Nguyen, a senior in biology, and Ariane Tom, a junior in materials science and engineering, heard about iGEM and caught the excitement of synthetic biology. At around the same time, Drew Endy, assistant professor of bioengineering and cofounder of iGEM, came to Stanford and later became the team's top faculty advisor.

The students were handpicked from fields ranging from chemistry and computer science to cross-disciplines such as biomechanical engineering. The team narrowed down the project over the last year and began building the machine in their lab on campus this month.

The team's bacteria are engineered to treat inflammatory diseases by balancing immune system cells in the intestine.

"One of the symptoms of bowel disease is a disruption in the ratio of two different types of T-cells, Th17 and T-regulatory cells, which are a part of your immune system," explained Suzanne Bartram, a sophomore member of the team. "Th17 cells have been known to increase levels of nitric oxide in the body, which leads to inflammation."

The students are designing the machine to detect the cause of inflammation and release a counteracting acid. "We're going to engineer the bacteria to secrete retinoic acid, which is shown to down-regulate Th17. This will bring the population of cells back down to a stable balance called homeostasis and decrease inflammation," she said.

"One of the side effects of bringing down the Th17 concentration is immunosuppression. Immunosuppression is what affects people with cancer and some cases of AIDS, when the immune system doesn't respond correctly or at all," said Anusuya Ramasubramanian, a junior in biomechanical engineering.

T-regulatory cells often prevent the immune system from a correct and timely response. The team plans to build in a gene code that maintains a healthy level of T-regulatory cells and Th17 cells, ensuring a balanced immune response.

Creating bowel-relief bacteria involves much more than stacking BioBricks. Genes must go through several lab procedures, such as culturing, extracting, transforming and quantitative testing in assays. Come assembly time, a "gene glue" enzyme called DNA ligase is added to bind two genes together as they bump into each other.

Several microns in size, the engineered bacteria would live in the gut just as many other helpful bacteria already live inside our bodies, Bartram said.

"What's really novel about our idea is that it's not a drug taken orally or injected by IV; it's an organism," Nguyen said. "Traditionally, you go to the doctor, get a prescription, and if it doesn't work out, you go back to the doctor and vary the prescription. This device monitors concentrations inside your body and responds in real time."

The team is hoping that bioengineered organisms like theirs will change the way people think about medicine. Doctors currently prescribe several steroids for intestinal diseases, which come with side effects. In severe cases, whole sections of the intestinal tract are removed. "Over a period of time, maybe several years, after cocktails of drugs, you may eventually reach a good balance if they don't take your colon out before then," Ramasubramanian said.

The summer project will culminate at the conference, where the top three teams win a giant gold, silver or bronze colored Lego block.

Visit the team's website for a full list of undergraduates, graduate students and faculty members.

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