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Ying Zhu
Ying Zhu, a chemist at Pacific Northwest National Laboratory, places a chip containing samples for analysis into the automated NanoPOTS system. (PNNL Photo / Andrea Starr)

Scientists have developed a technique that can analyze fluid from a single human cell to identify its proteins — which could open the way for tracking the progression of cancer one cell at a time.

The method is known as NanoPOTS, or “nanodroplet processing in one pot for trace samples.” It was developed by scientists at the the Department of Energy’s Pacific Northwest National Laboratory, and detailed in a study published in the German journal Angewandte Chemie.

“NanoPOTS is like a molecular microscope that allows us to analyze samples that are 500 times smaller than we could see before,” PNNL analytical chemist Ryan Kelly, the study’s senior author, said in a news release. “We can identify more proteins in one cell than could previously be identified from a group of hundreds of cells.”

In a follow-up email, Kelly told GeekWire that NanoPOTS can be used for research as well as diagnostics.

“As a research tool, the ability to identify and quantify hundreds or thousands of proteins with high spatial resolution (extending to single cells) will provide a wealth of information on how cancer progresses and how it responds to therapies,” Kelly wrote.

The technology can also come up with a profile of the proteins inside a tumor — either by looking at a tiny amount of biological material that can be extracted using a minimally invasive fine-needle aspiration biopsy, or by looking for circulating tumor cells in blood samples.

“This is something that could eventually be incorporated into routine blood tests,” Kelly said.

Nanoscale protein analysis could be combined with DNA analysis to open up a new frontier for cancer diagnostics, said Karin Rodland, a PNNL biologist who was not part of Kelly’s team.

“Mostly it would help health care by helping you identify targets for treatment in tumor cells,” she explained in an email. “If you have a targeted therapy, and you detect circulating tumor cells where the proteins tell you the tumor will be sensitive to the drug, you don’t need to know where the tumor is.”

The key to NanoPOTS’ promise is the ability to identify proteins in single cells, rather than having to pool together hundreds or thousands of cells in one sample.

With larger samples, it’s harder to find the proteomic needle in the haystack. Smaller samples pose challenges as well: Every time the sample is transferred, there’s a good chance that precious proteins are lost.

To minimize the loss, NanoPOTS uses an automated platform to capture and test droplets of fluid as small as 0.15 nanograms, or less than a ten-thousandth of a teaspoon.

A robot moves the droplets between tiny wells with micrometer-scale accuracy, minimizing the opportunities for proteins to get away. Then the material is fed into a mass spectrometer that separates out and measures each protein.

When researchers from PNNL and the University of Rochester Medical Center used NanoPOTS to analyze single human lung cells, they identified more than 650 proteins in each cell. Sample losses were reduced by more than 99 percent, compared to other technologies.

Medical applications are already in the works: Researchers have used NanoPOTS to get a closer look at the proteins involved in Type 1 diabetes in the pancreas. They’re developing a protein map of cancerous tumors, funded by the National Cancer Institute through the Beau Biden Cancer Moonshot Initiative. And they’re working with collaborators at Oregon Health and Science University on a blood test for circulating tumor cells.

NanoPOTS chip
The NanoPOTS chip contains multiple wells where proteins from single cells are separated out for further analysis. (PNNL Photo)

PNNL chemist Ying Zhu is the lead author of the paper published by Angewandte Chemie, titled “Proteomic Analysis of Single Mammalian Cells Enabled by Microfluidic Nanodroplet Sample Preparation and Ultrasensitive NanoLC‐MS.”

In addition to Zhu and Kelly, the authors from PNNL include Geremy Clair, Charles Ansong, William Chrisler, Yufeng Shen, Rui Zhao, Anil Shukla, Ronald Moore and Richard Smith. The University of Rochester’s Ravi Misra and Gloria Pryhuber are authors as well.

Teams from both institutions are part of a national research initiative known as the LungMAP project to develop a molecular atlas of the developing human lung during late pregnancy and early childhood.

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