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“We posit that this assay can potentially offer an outstanding biomarker to rapidly and inexpensively diagnose ME/CFS with high accuracy. In addition, this assay may offer a remarkable opportunity for the discovery of new treatments for this debilitating disease.”  Esfandyarpour and Davis 2019

In 2019, the nanoneedle was astoundingly accurate in plucking out ME/CFS patients.

What an exciting possibility the nanoneedle presented for the chronic fatigue syndrome (ME/CFS) community in the late 2010s. Not only did it suggest that a cheap and accurate diagnostic test for ME/CFS might be possible, but it was also being touted as a quick and easy way to assess treatments. We’ve heard little about the “needle” over the past couple of years, though. Was the nanoneedle a good idea gone awry?

It turns out that the nanoneedle is still alive and well. A product of Ron Davis’s Stanford Genome Technology Center, the “nanoneedle” has jumped oceans, and thanks to funding from ME Research UK and the ME Association, it’s back in action in the UK.

The nanoneedle first showed up in the scientific literature back in 2013 when a paper described it as an “ultra-sensitive, real-time” biosensor with the potential to cheaply detect biomarkers at a far more sensitive level than had ever been done before.  By 2016, a redesigned and improved nanoneedle was described as a rapid, inexpensive, highly sensitive alternative to more expensive or less sensitive devices available. The authors called it “an excellent candidate for point-of-care diagnostics”.

Davis and  Esfandyarpour then tweaked the needle to work on ME/CFS. Focusing on the energy deficits associated with ME/CFS, they put ME/CFS patients’ cells into an energetically stressful state by immersing them in a salt solution. As the cells expended high amounts of ATP to maintain homeostasis, they used the nanoneedle to compare ME/CFS patients’ cells with healthy controls.

In 2019, Esfandyarpour and Davis published their nanoneedle findings, “A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)“, in the prestigious Proceedings of the National Academy of Sciences (PNAS) journal.

Threading the Needle: Nanoneedle Scores Big in First ME/CFS Test

They found that the test – which delivered 40,000 data points – wasn’t just accurate – it was astoundingly accurate – generating probability factors rarely seen in medical research (p<0.0000506). The altered electrical impedance or resistance found in the ME/CFS patients’ cells compared to the healthy controls suggested the ME/CFS patients’ cells had been put into a state of post-exertional malaise.

Sodium Potassium pump

Klaus Wirth and company believe problems with the sodium potassium pump play a key role in ME/CFS. (Photo from Wikimedia Commons – Blausen Blausen.com staff (2014). “Medical gallery of Blausen”)

While the needle was able to differentiate people with ME/CFS from healthy controls, the biological implications of the findings were unclear; i.e. while the researchers knew something had changed in the ME/CFS patients’ cells when they were put in the salt solution compared to the healthy controls, they didn’t know what.

In 2019, the authors put forth some ideas (Na/K ATPase pump, inflammation, phospholipid synthesis, endoplasmic reticulum stress) that have only gotten more intriguing over time. Problems with the Na/K ATPase pump play a central role in the Wirth/Scheibenbogen/Lohn series of ME/CFS hypothesis papers, Maureen Hanson’s and Ian Lipkin’s labs have uncovered problems with phospholipid synthesis, and NIH researchers recently made a big splash when their findings suggesting that ER stress might play a big role in ME/CFS.

WASF3 – NIH Researchers Find New Mitochondrial Abnormality in ME/CFS

The idea that a cheap and easy-to-use diagnostic test might have been developed led then NIH chief Francis Collins to crow over the early NIH funding that helped develop the device:

“In @stanfordmed study, researchers developed new blood-based test that positively identified participants w/#MECFS. If findings can be validated in larger study, it may provide a diagnostic tool for clinicians & a target for new ME/CFS Txs. #NIH-funded https://stan.md/2IU7nYN“ Francis Collins

THE GIST

  • The nanoneedle presented an exciting opportunity for the chronic fatigue syndrome (ME/CFS) community in the late 2010s. Not only did it suggest that a cheap and accurate diagnostic test for ME/CFS might be possible, but it was also being touted as a quick and easy way to assess treatments.
  • In a 2019 study Ron Davis and Rahim Esfandyarpour put ME/CFS patients’ cells into an energetically stressful state by immersing them in a salt solution. As the cells expended high amounts of ATP to maintain homeostasis, they used the nanoneedle to compare ME/CFS patients’ cells with healthy controls.
  • They found that the nanoneedle – which delivered 40,000 data points – wasn’t just accurate – it was astoundingly accurate in differentiating ME/CFS patients from healthy controls and generated probability factors rarely seen in medical research (p<0.0000506).
  • The data suggested the ME/CFS patients’ cells had been put into a state of post-exertional malaise. It wasn’t clear, though, what was happening in the ME/CFS patient’s cells when they were stressed.
  • An inability to secure funding from the NIH appears to have stopped the work from fully proceeding and no papers have been published on the needle since 2019.
  • UK researchers, however, were taking note and ME Research UK and the ME Association recently announced they were co-funding a 12-month study that will attempt to expand on and validate the Davis team’s findings.
  • The team has already made significant steps forward. Using “a more robust approach”, the UK researchers reported they have already replicated the 2019 results and have done so not just with ME/CFS patients and healthy controls but with multiple sclerosis patients as well. Calling the findings “highly significant”, the UK researchers stated they presented “a clear marker of pathology“.
  • They will attempt to go beyond the initial findings in the new grant and identify the unusual changes occurring in ME/CFS patients’ cells when put under stress. That could give us clues as to why ME/CFS patients have trouble generating energy and functioning properly at the cellular level.
  • A successful study could also, one would hope, help achieve a goal of the original nanoneedle – finding a way to quickly assess the effects of treatments on ME/CFS patients’ cells and uncover biological signatures.
  • Could we have a long-sought-after biomarker in a year? Time will tell. In the meantime, congrats to ME Research UK and the ME Association for banding together to fund this most interesting effort.
Collins neglected to mention, though, that subsequent grant applications to use the device in ME/CFS were rejected. The ME/CFS work with the device was entirely funded by the Open Medicine Foundation.

The inability to get funding to improve the device, plus Esfandyarpour’s move to another University, appears to have left the nanoneedle in limbo. No studies have been produced since 2019.

UK researchers, however, were taking note and ME Research UK and the ME Association recently announced they were co-funding a 12-month study that will attempt to expand on and validate the Davis team’s findings.

Five researchers, Dr. Robert Dorey, Dr. Fatima Labeed, and Professor Michael Hughes from the University of Surrey, and Dr. Eliana Lacerda and Caroline Kingdon, from the London School of Hygiene and Tropical Medicine and the UK ME/CFS Biobank were awarded the grant.

The grant goes to a mixture of seasoned ME/CFS experts and researchers new to the field. While Lacerda co-founded the CureME team with Caroline Kingdon, and co-created the UK ME/CFS Biobank (UKMEB), Dr. Robert Dorey is a nanomaterials expert who has not participated in ME/CFS research before.

While the specifics of the grant are unclear, the brief grant description indicates the team has already made significant steps forward. Using “a more robust approach”, the UK researchers report they have already replicated the 2019 results and have done so not just with ME/CFS patients and healthy controls but with multiple sclerosis patients as well. Calling the findings “highly significant”, the UK researchers stated they presented “a clear marker of pathology“.

They will attempt to go beyond the initial findings in the new grant and identify the unusual changes occurring in ME/CFS patients’ cells when put under stress. That could give us clues as to why ME/CFS patients have trouble generating energy and functioning properly at the cellular level. A successful study could also, one would hope, help achieve a goal of the original nanoneedle – finding a way to quickly assess the effects of treatments on ME/CFS patients’ cells and uncover biological signatures.

Could we have a long-sought-after biomarker in a year? Time will tell. In the meantime, thanks to the UK researchers for pursuing this, and congrats to ME Research UK and the ME Association for banding together to fund this most interesting effort.

 

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