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Gauging the potential of a “micro” window into disease

With every beat of a person’s heart, blood whooshes through their vessels, transporting blood cells, immune cells, oxygen, and nutrients throughout the body. Over time, as blood pulses in and out of the heart, it accumulates other materials—hormones, cells from various organs, and loose bits of DNA, for example. Among those molecules that hitch a ride around the body in the circulatory system are microRNAs, small pieces of RNA that play a role in controlling which proteins any given cell manufactures. Depending on a person’s health, different microRNA molecules might be free-floating in the blood; cancerous tumors have been shown to produce unique patterns of microRNAs and specific microRNA imbalances have been suggested to play roles in heart disease, Alzheimer’s, schizophrenia, and other diseases. So can a blood test help diagnose or track the status of these conditions through measuring levels of circulating microRNAs? That’s what a new PNAS Early Edition paper set out to answer.

Williams et. al. wanted to paint a picture of the landscape of microRNAs that are in a person’s blood. How many microRNA molecules are there in a milliliter of blood? How many microRNAs come from any particular tissue? How much do they vary between people?

Previous studies of circulating microRNAs had mostly relied on methods that required researchers to fish particular microRNAs out of the blood. Levels of two different microRNA molecules could be compared, for example, by specifically measuring those molecules.

“You only find those miRNAs that you’re looking for when you do it that way,” says first author Zev Williams of the Albert Einstein College of Medicine. “You can get relative numbers but you can’t quantify the absolute amounts of all microRNAs.”

So, in their new work, Williams and his colleagues developed and fine-tuned a new combination of methods that allowed them to isolate, characterize, and quantify the tiny concentrations of every single microRNA in a blood sample. To test out the usefulness of the approach, and begin answering basic questions about circulating microRNAs, they needed a simple model system to study. Rather than taking on a broad, complex condition like a cancer or chronic disease, they turned to something more commonplace—pregnancy—and they set out to study the microRNA that originates in the placenta during pregnancy.

“The placenta is actually one of the best models you could possibly find to mimic a tumor,” says Williams. The cells in the placenta have unique genetic signatures from the mother’s own cells, instead matching those of her fetus. And the placenta itself can easily be measured and sampled after birth so that its genetics can be compared to the patterns found in circulating microRNAs, Williams explains. Moreover past studies have concluded that women with preeclampsia—a condition that can develop during pregnancy— have different levels of some microRNAs after birth than is found in other women. So if placental microRNA could be measured

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in blood samples of pregnant women, it could offer a new way to test for the condition.

The team collected blood samples from pregnant women, their husbands, and non-pregnant women. After the pregnant women gave birth, they directly measured the microRNAs in the placental tissue.

“What we found is that by detecting subtle changes to the miRNAs we can actually fingerprint the individual placentas,” says Williams. After sequencing every microRNA found in each sample, they identified clusters of microRNA molecules that are unique to the placenta and which they were able to identify and quantify in the blood sample from pregnant women. “This hints that we might be able to track alterations in the placenta due to stress or disease,” says Williams. It also suggests that microRNA unique to cancer, for example, could be detected in blood.

When the researchers began comparing microRNA from the placentas themselves to the microRNA in the mother’s blood, however, they found that it wasn’t always a perfect match. In general, most of the same microRNA molecules found in the placenta were also found in the blood, but the relative levels weren’t the same—the ones found most concentrated in the placenta weren’t the same found most frequently in the blood. The observation reflects how little is still known about circulating microRNAs in general, Williams says, and how many more questions need to be answered before clinical applications can even be pondered.

“We now know that we can profile these RNAs in circulation,” he says. “The next step is to actually move toward answering more basic questions.”

A larger sample size is needed, he says, to provide a baseline of normal microRNA profiles across variables such as race, weight and sex and to understand how much a person’s microRNA landscape varies over time. But through the proof-of-concept that levels of all circulating microRNA can be quantified at once, the team has offered a way to move toward answering these questions and discovering whether microRNAs hold any promise as windows into disease.

 

Categories: Applied Biological Sciences | Medical Sciences
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