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Chemical Sensing

Biosensor tracks real-time blood levels of phenylalanine in rats

Aptamer-based sensor takes step toward real-time monitoring of the amino acid for people with phenylketonuria

by Louisa Dalton, special to C&EN
March 10, 2021 | A version of this story appeared in Volume 99, Issue 9


Schematic showing an aptamer connected to a gold electrode wrapping around phenylalanine and bringing methylene blue close to the electrode to initiate a rapid electron transfer.
Credit: Adapted from Anal. Chem.
When a nucleic acid aptamer bonded to a gold electrode folds around phenylalanine, it drops methylene blue close to the electrode. The electrochemical signal spikes, creating a sensitive, reversible signal.

People with the genetic disorder phenylketonuria (PKU) can develop dangerous blood levels of the amino acid phenylalanine, requiring them to strictly control their protein intake. A new biosensor that detects the rise and fall of the amino acid in the body is a step toward a device that would allow people with PKU to personalize their own nutrition and therapy (Anal. Chem. 2021, DOI: 10.1021/acs.analchem.0c05024). Tested in rats so far, the measurement tool should also speed up research on future PKU therapies, researchers say.

Photo of a thin sensor threaded through a blue plastic housing sitting next to a 5-cent Euro coin.
Credit: Julian Gerson
A needle-thin sensor (attached to a blue plastic housing and shown next to a €0.05 coin for scale) can be inserted into a rodent vein to track phenylalanine concentration.

Most folks never need to think about their phenylalanine levels. But about 1 in 16,000 people in the US are born with a faulty phenylalanine hydroxylase enzyme and cannot properly break down the amino acid. Every time they eat protein, their blood phenylalanine level rises, which disturbs the brain’s amino acid balance and can cause permanent neurological damage. The disease is managed with an onerous, low-protein diet and sometimes an injectable enzyme therapy. People with PKU test their blood up to twice a week, generally with a mail-in fingerprick blood test, and must wait another week for results. “If people with this disease had the kind of real-time information that diabetics use, we believe it could significantly improve both their treatment and their quality of life,” says Kevin W. Plaxco, a bioengineer at the University of California Santa Barbara.

Plaxco and his group adapted an electrochemical sensor that they developed about 5 years ago to measure drug molecules in the blood of live rats. They started with an existing aptamer—a strand of nucleic acids that captures a target molecule—which binds to phenylalanine. Then they fastened one end of the aptamer to a gold electrode and tagged the other end with methylene blue. When the aptamer binds and folds around phenylalanine, it swings the methylene blue reporter down, making its electrons more available to the electrode, spiking the current. The binding is reversible, selective, and sensitive enough to pick up small concentration changes.

Plaxco’s group inserted the sensor, about the width of a sewing needle, inside the jugular veins of four anesthetized rats and injected them with phenylalanine to simulate a meal. The sensor took a reading every 12 s and measured phenylalanine levels quickly spiking and then decreasing exponentially over the next 30 min.

Better-resolved kinetic studies could reveal significant details about phenylalanine metabolism, both across populations and in individuals, Plaxco says. He hopes to make a version for clinical studies to determine a person’s individual phenylalanine metabolism rate and study how that might be influenced by various factors. His ultimate goal is to develop a wearable device for people with PKU that can take measurements continuously from just under the skin, like current glucose meters do; he’s working with companies to commercialize the technology.

A real-time phenylalanine sensor would also help make animal studies easier, says Anne M. Andrews, who studies neurotransmitter pharmacology at the University of California Los Angeles and created an in vitro sensor for phenylalanine using the same aptamer (ACS Sens. 2019, DOI: 10.1021/acssensors.9b01963). “We don’t even have the basic biology down, to be honest with you, because we’ve never been able to make measurements in this kind of time frame,” she says.

Andrews points out that rats and mice are regularly used as animal disease models, yet taking recurring blood draws is even more impractical in rodents than in humans. “They have very little blood in their body. You can maybe take two or three or four samples, and that’s it,” she says. “I can think of a lot of experiments going forward that would be really interesting to do in these animals with that kind of temporal resolution.”


This story was updated on March 11, 2021, to note that the Plaxco group did not design the aptamer for phenylalanine but rather used one that had been previously identified.


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