Tracking Bioengineered Bacteria Through The Body Using Ultrasound

Each of our hundreds of trillions of cells is as complex as a big city, and the mere shape of our internal organs reveals little about the true complexity of life. Unfortunately, you can’t “see” biochemistry, at least not with the naked eye. However, advances in molecular biology are literally illuminating the chemistry going on inside living tissues.

Scientists at the Shapiro Lab at Caltech have engineered bacterial cells that are exceptionally visible to ultrasound imaging. This technology could finally allow scientists to “watch” the biochemistry going on deep within living animals.

Since the 1990’s, there has been a fluorescent protein revolution in molecular biology. These fluorescent proteins are engineered to emit light from cells that express whatever gene scientists want to study. Unfortunately, unless your animal is translucent, they are not much use in illuminating the chemistry of internal organs. If you want to know what’s going on deep inside, you are limited to the static and specious snapshot of a dead and dissected animal.


Mouse engineered to express Green Fluorescent Protein (GFP)

Ultrasound imaging, on the other hand, is a great non-invasive technique to see inside a living body. This is the same technology that has us staring at amorphous black and white images trying to figure out how cute our future child will be. Ultrasound imaging uses echolocation, emitting sound waves (at a much higher pitch than we can hear) and recording their reflections from different internal tissues, turning them into a 3D image. Until now, ultrasound imaging only revealed internal structure, not the chemistry, gene expression, or types of cells in those deep tissues. However, the Shapiro Lab has engineered bacterial cells that specifically ‘light up’ under ultrasound.


Embryo at 14 weeks

How? Tiny balloons. Some bacteria in nature already make tiny gas-filled structures inside their cells to help regulate their buoyancy. Because of their size, these balloons happen to vibrate at the same frequency as the ultrasound wave, strongly reflecting the ultrasound signal. Obviously, these natural structures did not evolve with ultrasound technology in mind, so they had to be further engineered or tuned like tuning a guitar string or drum head. The Shapiro Lab did this by combining pieces of genes from different bacterial species to get the best ultrasound signal. Despite occupying roughly 10% of the cell’s volume and 1% of the cell’s mass, the balloons only marginally impaired the growth and movement of the bacteria.

An additional feature of these balloons is that they collapse when subjected to a suddenly strong pulse of ultrasound, like a glass shattered by an opera singer’s voice. The authors demonstrate that the balloons can be engineered to collapse at different pressures and frequencies, enabling different populations of cells to be distinguished within the same tissues, adding color to the gray ultrasound image.

As a proof of concept that these bacteria can be observed in live animals, the Shapiro Lab injected a chunk of gel that contained the engineered bacteria into the colon of a mouse. They used a species of bacteria that occurs naturally in the gut and is often used in humans to treat digestive disorders. Indeed, shape and location of the bacterial gel inside the mouse could be imaged with high resolution.

They were also able to image cancer tumors using this technology. Special strains of bacteria have already been engineered to bind to cancer tumors and even inhibit their growth. By giving these cancer-tracking bacteria the balloon-making genes, they successfully imaged a mouse tumor using ultrasound.

Bacteria can be easily engineered to stick to a variety of specific tissues, and have the potential to serve as ultrasound homing beacons for imaging various tissues in both research and medical therapy. Other applications include tracking the spread of newly introduced bacteria into our gut and the dynamics of our bacterial ecosystem. Many medical disorders are caused by imbalances in our gut bacteria and require the introduction of new bacteria into our body to correct the imbalance. Better understanding how and where these bacteria spread within us will better direct future treatments and innovations.

One of the Shapiro Lab’s most ambitious goals moving forward is engineering animal cells to manufacture these ultrasound balloons. However, can animal cells make this bacterial structure? Would the presence of these balloons affect the way animal cells behave? Would they stimulate an immune response? Can they be used in a therapeutic context? If these hurdles can be cleared, the impact of ultrasound markers like these could be an extraordinary new tool for research and medicine.


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