The drug heparin is widely used to prevent blood from clotting in medical procedures ranging from dialysis to open-heart surgery. With a $6 billion market, it is one of the most common drugs used in hospitals today. But its widespread use belies its crude origins: more than 90 years after it was discovered, heparin is still made from pig intestines. But a new microfluidics chip, which mimics the actions of one of the cell’s most mysterious organs, may help change that. Researchers at Rensselaer Polytechnic Institute in Troy, NY, have created the first artificial cellular organelle and are using it to better understand how the human body makes heparin.
Scientists have been working to create a synthetic version of the medication, because the current production method leaves it susceptible to contamination–in 2008, such an incident was responsible for killing scores of people. But the drug has proven incredibly difficult to create in a lab.
Much of the mystery of heparin production stems from the site of its natural synthesis: a cellular organelle called the Golgi apparatus, which processes and packages proteins for transport out of the cell, decorating the proteins with sugars to make glycoproteins. Precisely how it does this has eluded generations of scientists. “The Golgi was discovered over 100 years ago, but what happens inside it is still a black box,” says Robert Linhardt, a biotechnologist at Rensselaer who’s been working on heparin for nearly 30 years and is lead author of the new study. “Proteins go in, glycoproteins come out. We know the enzymes that are involved now, but we don’t really know how they’re controlled.”
To better understand what was going on inside the Golgi, Linhardt and his colleagues decided to create their own version. The result: the first known artificial cell organelle, a small microfluidics chip that mimics some of the Golgi’s actions. The digital device allows the researchers to control the movement of a single microscopic droplet while they add enzymes and sugars, split droplets apart, and slowly build a molecule chain like heparin. “We can essentially control the process, like the Golgi controls the process,” Linhardt says. “I think we have a truly artificial version of the Golgi. We could actually design something that functions like an organelle and control it. The next step is to make more complicated reaction combinations.”
“People have had bits and pieces of the toolbox for making these important carbohydrates, but one thing you should potentially do is try to emulate nature, or at least figure out how it works,” says Paul DeAngelis, a biochemist and molecular biologist at the University of Oklahoma who was not involved in the research. “The miniaturization that they’re doing–having little bubbles of liquid fuse and go to different compartments with different catalysts under different conditions–that’s how your body and the Golgi apparatus works. It’s a nice model.”
Currently, researchers know what heparin looks like and what enzymes are required to make it, but they don’t quite know how it’s made. “It’s like having all the materials and tools required to build a house and knowing what the final house looks like, and then having someone say, ‘Okay, go build the house,’” Linhardt says. “What we need is a blueprint. We need to know how these tools function together, how the house is assembled.” He likens the microfluidics chip to a house-building DIY reel, one that “tells us how to hammer nails, how to saw, how to assemble struts, how to put walls in.” By testing reagents in different amounts, with different reaction times, the artificial Golgi may be able to teach them how to synthesize heparin and other molecules in a laboratory setting.
“It’s a fusion of engineering and biology,” says Jeffrey Esko, a glycobiologist at the University of California, San Diego. “One can do this in test tubes, but the chip provides a way to automate the process on a microscale.” The chip also allows for precise control over each individual interaction, and at a small scale.
With the help of their microchip and substantial funding from the National Institutes of Health, Linhardt believes that they should be able to bring bioengineered heparin into clinical trials within the next five years.
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