Nanoelectric device could lead to a diagnostic blood test for ME/CFS

Nanoelectric device could lead to a diagnostic blood test for ME/CFS

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Last week, Dr Ron Davis’s team published a pilot study showing remarkable results for their nanoneedle device. Strikingly, there was no overlap between the results for 20 ME/CFS patients and those for 20 healthy controls, something that is almost never seen with this illness.

A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

R Esfandyarpour, A Kashi, M Nemat-Gorgani, J Wilhelmy and RW Davis. 2019

The nanoelectric blood test

Nanoelectric wafer
Nanoelectric silicon wafer that researchers use to test samples. Black lines are not part of the wafer. (Figure 2C from the paper)

The research used nanomanufacturing techniques to embed large numbers of tiny electrodes within a silicon wafer. Each electrode, or nanoneedle, is comparable in size to a cell.

The researchers created a simplified blood sample for each patient that consisted of white blood cells (immune cells) in plasma, but without red blood cells and platelets. The scientists added each sample to a silicon wafer, and the electrodes then measured electrical impedance.

Impedance is a measure of how difficult it is for the electrical current to pass through the cells and/or plasma next to the electrodes. Critically, in the nanoelectric set-up, the authors say that change in impedance “results from cellular and molecular interactions”.

The key element of the test, which exposes the dramatic difference between patient and control samples, is to force the cells to use more energy than normal. The aim was to replicate at the cellular level a key aspect of ME/CFS: the way problems emerge when energy demands ramp up.

The researchers forced the cells to use more energy simply by adding sodium chloride — table salt — to the sample. In the jargon, the salt acts as a “hyperosmotic stressor”.

Some of the extra salt enters the cell and, through osmotic pressure, the salt draws water with it, causing the cell to swell up. The cell has to combat this tendency and so must use energy to power a molecular pump that pushes the extra salt back out of the cell.

The different response seen between the samples of patients and controls is striking. There is little change in electrical impedance for healthy cells. But after half an hour or so, there’s a huge increase in impedance for the samples from ME/CFS patients.

Electrical impedance trace for samples from a patient and a control
Electrical impedance change over 2.5 hours for samples of a bedbound patient and a healthy control (Figure 1C from the paper; some labels enlarged for clarity)

Lead author Rahmim Esfandyarpour told STAT News, “we’re forcing [patients’ cells to consume energy] and they are not happy… their reaction is different from the reaction of healthy cells”. The healthy cells seem to manage the situation comfortably.

Strikingly, the increase in impedance for every single patient’s sample was substantially higher than for even the highest increase seen for any of the healthy controls’ samples.

Impedance change from baseline to plateau for samples from each of 20 patients and 20 controls. (Figure 2C from the paper; some labels and yellow band addd by me.)

It is the amount of clear daylight between patients and controls (indicated above by the yellow band in the graph) that makes these results so remarkable and so interesting. At the recent NIH ME/CFS conference, Dr Anthony Komaroff, a professor at Harvard Medical School, said that such a difference is “a clue to some underlying biology that could be causative of the symptoms of the illness.”

To make the findings more impressive, the authors also showed that the findings are highly reproducible. “If you test the same patient a week or month later, you get the exact same signal”, senior author Ron Davis told Medscape Medical News.

The study authors say that they believe these findings are unique to ME/CFS.

Commenting on the study, Chris Ponting, Professor of Medical Bioinformatics at Edinburgh University, said, “Excitingly, they appear to have discovered a distinguishing feature of ME/CFS, and one that can be measured simply and cheaply.”  However, he stressed the need for replication of results and the need for sick controls. He said, “results should be replicated in a second cohort of individuals” and added that the device should be tested to see “whether it sets apart ME/CFS not just from general health but also from other disorders.”

Happily, the authors are planning to do just this. They have announced that they will be running a replication in a larger group of patients, — and will be including people with similar diseases as controls.

The researchers admit that they don’t know what biological differences lie behind the dramatic difference that the nanoelectric device shows between patients and controls. They speculate that they could be changes in the outer membrane of patients’ cells, amongst other possibilities. But the researchers are planning experiments to try to uncover the biology. The new work could be critical in understanding ME/CFS.

The authors are also working on adapting the technology to create a user-friendly platform for screening potential drugs. The basic idea is that any drugs that can make ME/CFS cells behave like healthy ones might be therapeutic in patients.

And the team have already started screening drugs that have already been approved for other conditions. If any of these prove effective in ME/CFS, they would be available to ME/CFS patients in a shorter timescale because they would have already passed through much of the regulatory process.

One of the most important uses for this new technology, if it proves to be accurate and if the differences are specific to ME/CFS, would be in helping to make robust diagnoses.

Davis’s team are already trying to adapt the technology so that it could be used in any doctor’s office (for now, it needs to be done in a lab). And the nanoelectric chips are very cheap to make commercially, so the test should be affordable and widely available.

In conjunction with existing measures, such as the Canadian Consensus Criteria, the nanoelectric device would make it relatively straightforward for physicians without specialist expertise to make a diagnosis.

Research in the US indicates that perhaps 80% of people with ME/CFS are undiagnosed. So there could be a million Americans who are sick with ME/CFS but don’t know what’s making them ill, and many more such people worldwide.

With a diagnosis, people could at least get advice on how to manage their condition more effectively until good treatments are available. That could improve life for a great many people, with the potential for making a huge difference once there are effective treatments.

9 thoughts on “Nanoelectric device could lead to a diagnostic blood test for ME/CFS

  1. Let’s hope NIH funds Ron and Rahim’s June grant application!

  2. Simon. This is great as usual. Thanks! Ron said something about these results being very strong. That the P value is 1×10 to the -9th or something like that. And did I hear/read that somehow this study is equivalent to a much larger study, that testing a larger cohort of ME CFS patients is not necessary? I’m not a scientist. I understand that he’s saying these results are extremely strong with no chance of statistical error. Could you explain a bit more?

    1. Thanks, Leela

      That degree of separation between patients and controls is quite astonishing and so I am not surprised by the quoted P values. However, I don’t think that’s the same as saying a replication is not needed. 20 is still a small sample, and may not be representative of the wider patient population (what you really want to know from a P value is “is this finding generally true?”)

      I think every scientist commenting on the study that I saw, including Chris Ponting and Maureen Hanson, pointed to the need for replication. So I don’t think it’s safe to assume that we have a final answer on this. In any case, the team have said they will be attempting a larger scale replication.

      1. The result is good enough that more samples using the same lab and same technicians won’t prove much. With a p-value so low the only remaining sources of error are handling mistakes and research fraud. Which is why a replication by another lab would be extremely valuable.

        1. Largely agreewith that, but might be hard to find another lab capable of making one of these! Simon

    2. Yes, there was so little variance that a fairly strong P value (probability that this is due to chance) suggested they could have done the study with fewer samples.
      More is always better: mostly, with Statistics.

  3. I’m thinking about the types of conditions this technique could be used to test. EMR sensitivity comes to mind. There is no test for this condition which is also considered generally highly suspect, just like ME/CFS. Many patients, including myself suffer from EMR. It would be interesting to have a comparison group who do not have ME/CFS but have EMR. Any thoughts?

    1. It doesn’t seem N obvious one to me. The test was Developed to target the post exertional issues specific to ME/CFS

  4. Very clear easily readable explanation; thank you. I’m wondering what “EMR” is?
    I’ll be interesting to see the results from diseases which potentially overlap with ME e.g. Lyme and MS.
    Karl Morten is one of the authors of a paper proposing elevated intracellular phenylalanine as a diagnostic test [Google – Raman spectroscopy ME phenylalanine – and you should find the abstract]. Phenylalanine is one of the amino acids which is used for cellular energy production in ME i.e. rather than the normal glucose [Chris Armstrong – 2015].

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