A nanoelectronics-blood-based diagnostic biomarker for ME/CFS (2019) Esfandyarpour, Davis et al

Some updates:

From the May 2019 IiME conference
Andy said:
Ron Davis, Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford - Establishing new mechanistic and diagnostic paradigms for ME/CFS

...
Nanoneedle
  • Added 10 patients and 10 controls to the cohort being tested.
  • Screening patients with other diseases.
  • Wants to design and build high throughput electronics to take the current cost from $30k and each device being able to run 2 samples at a time, to a $200 cost able to run 100 samples at a time.
  • Also wants to design and fabricate better chip with easier-to-use electrical connections.
  • Plans to screen FDA approved drugs.
...

Copaxone and SS-31, when added to patient blood, nanoneedle results looks like healthy controls.
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From a New Zealand radio interview 25 June 2019
Hutan said:
Rough notes - not perfect.
Interviewer: CFS is a debilitating, mysterious and often minimalised illness. Many people with it complain that their condition is regarded as imaginary. There has been a lack of a reliable test. Dr Ron Davis has identified a diagnostic test, in a small pilot study.

In 2013 Davis was ranked amongst greatest living inventors, many advances in the field of genetics can be traced back to him. When his son Whitney became sick, he turned his attention to CFS.


Davis: Patients don't look sick but are severely affected. On standard tests they seem perfectly healthy. Whitney is bed-bound, tube-fed and yet on standard tests he looks healthy. The Institute of Medicine suggested that 80% of patients are undiagnosed. Currently diagnosis requires experts and there aren't many experts. A diagnostic test will help validate patients and help doctors figure things out.

Whitney took several years to get diagnosed and that was only because he worked at it and I encouraged him. Initially we thought that doctors would figure it out. I re-focussed my work on ME/CFS, wrote multiple grants without success. Teamed up with OMF, a charity, that could provide funding.

The disease is multi-system, brain, immune, gut. Complicated. But I'm optimistic that we can cure this disease.


Interviewer: this new diagnostic tool..


Davis: Had already developed this device, chip size is so small you can't really see them, they are on a wafer. It was being tested for use in assessing the utility of drugs acting against cancer and bacteria. Saw that patients can't produce energy. Adding salt to the cells required the cells to use energy pumping the salt out, so it stresses the cells.

Need to make the device 'next-generation', closed in (i.e. to make it user-friendly, more robust). The device hasn't been tested on other diseases.

There are 8 other devices, not so far along. Hopefully they can be used to separate CFS from other diseases.

We have already found a couple of drugs that seem to help the cells survive the salt stress. We want to find an already approved drug that helps, to speed the process.

Next thing is to find the cause. We are collecting a huge amount of data from patients. Have found some genetic abnormalities. Of the 66 patients investigated, all have the same mutation. You observe, then ask 'what's causing that?' and iteratively track back to the primary cause.

It doesn't appear that we will need to continuously treat or that there is permanent damage. We have one patient who was bed bound and she is now over it; she can run 10 miles a day.


Interviewer: A listener has responded. They thank you Ron for your efforts, especially when they have taken you away from the care of your son. Has a son, bed-bound who has missed his secondary school years. Medical training continues to perpetuate the idea that CFS/ME is psychological issue.


Davis: Yes, but things are improving. Scientific data shows it's not psychosomatic. There are many labs working on this, finding molecular abnormalities that cannot be caused simply by thinking. That view that the condition is psychosomatic, it's absolutely incorrect, I would call it barbaric. Even in 2015, the Institute of Medicine report said that it is clearly not psychosomatic. We need to update the thinking and we then need to find out how to treat. Initially, we can treat the symptoms, and most doctors can treat the symptoms. Many patients seem to have mast cell activation - and there are drugs to alleviate that.


Interviewer: What can patients do?


Davis: Advocacy. Phoenix Rising site, Open Medicine Foundation. We run a symposium every year - live-streamed and archived on You Tube. We have just established another collaborative centre on Harvard, they have a big hospital there so work can be done with patients. And we have a new site in Sweden, they are doing spinal taps. There is progress, but we need money.
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Ron Davis talks about ME patients having the symptoms of Mast Cell Activation in the piece above, and that they can be treated.

Is anyone having treatment for mast cell activation? I have written in another thread that I think I may have developed this and would be grateful for any comments. Does anyone know what treatments he’s referring to?

https://www.s4me.info/threads/due-t...en-could-mcas-be-in-the-mix.9897/#post-179242

ETA: ME added
 
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JAMA: Biomarker Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome affects at least 2 million people in the United States. Despite its prevalence, there’s no laboratory test for the disease, and its diagnosis is based on symptoms like exhaustion, unrefreshing sleep, and light sensitivity. For patients with this debilitating condition, getting a diagnosis is often a long and expensive process. Now, a long-awaited biomarker-based test for the mysterious disease could be on the horizon.
 
Kalliope said:
JAMA: Biomarker Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome affects at least 2 million people in the United States. Despite its prevalence, there’s no laboratory test for the disease, and its diagnosis is based on symptoms like exhaustion, unrefreshing sleep, and light sensitivity. For patients with this debilitating condition, getting a diagnosis is often a long and expensive process. Now, a long-awaited biomarker-based test for the mysterious disease could be on the horizon.
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Thanks for the article.

Perhaps related to a request yesterday to return for yet another blood draw at Stanford. I don't know anything more, however. :cookie: (I always eat a cookie after a blood draw)

Edit: The blood draw turned out instead to be for a metabolic trap study.
 
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Andy said:
Stanford Medicine Twitter have reposted the article about this study.

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Any ideas how long the process will take until I can get the test privately or go to my GP and ask for it? I should imagine a very long time, no?
 
Following a question by @FMM1 on another thread I thought I would go looking to see if there was any updated info on the Nanoneedle work.
FMMM1 said:
Anyone heard anything about the nano-needle?
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It was one of the applications to NIH that was reported on in the summer of 2019.
Relieving an Overworked Nanoneedle – the nanoneedle has been overwhelmed. Diagnostics, drug testing, looking for Waldo (the bad factor) in the blood – it’s just been asked to do too much. It needs to be updated so that it can run many more samples, etc. That’s what Rahim Esfandyapour’s application intends to do.
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https://www.healthrising.org/blog/2019/08/06/harvard-chronic-fatigue-syndrome-hub-hidden-gem/

This was an update from Ron Davis on PR in Dec 2019
What is now necessary is to fabricate a new electronic control system that can collect the data from the nanoneedle allowing it to collect data from up to 100 chips simultaneously. That way, all the fractions from the blood sample of one patient can be run simultaneously. Rahim Esfandyarpour, who developed the nanoneedle, has been working on this.

However, since Rahim has taken a professorship at UC Irvine, he has had to set up his whole new operation, get new students, and train everyone. He has been coming up to Stanford and collaborating with me every week. He has submitted a grant to NIH for this project. Meanwhile, he has been funded by OMF to pursue this new machine and to make new chips. He has now delivered a large new batch of chips.
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The full statement about the work can be found here.
https://forums.phoenixrising.me/threads/nanoneedle-update-finding-whats-in-the-blood.78592/

I assume it didn't get accepted for NIH funding as no news on the application since then. With NIH funding Dr. Esfandyarpour would have very good motivation to assign students to work on it and progress could be accelerated. I have no idea if anybody is assigned to do the work described although it does seem from the update that someone is working on it. Maybe the application can be resubmitted?

This is Dr. Esfandyarpour's bio at UCI Engineering school for those interested.
https://engineering.uci.edu/users/rahim-esfandyarpour

This is a description of his research group. I see no pictures of the nanoneedle, and no mention of it as a specific project. Biggest emphasis is on wearable sensors for health.......
https://faculty.sites.uci.edu/esfandyarpourlab/

There is/was an opening in his group which is for a post doc to work on Organ-on-chip work which is a joint project with Stanford. It is not for nanoneedle.
https://www.linkedin.com/posts/rahi...tdoc-opening-ugcPost-6631684996530868224-y4KB

And there was another Phd student advert 5 months ago, for a position starting in the fall 2020. Perhaps this will include nanoneedle work?
https://www.linkedin.com/posts/rahi...ing-to-uci-activity-6602064237529567232-lpMv/
 
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wigglethemouse said:
Following a question by @FMM1 on another thread I thought I would go looking to see if there was any updated info on the Nanoneedle work.

It was one of the applications to NIH that was reported on in the summer of 2019.

https://www.healthrising.org/blog/2019/08/06/harvard-chronic-fatigue-syndrome-hub-hidden-gem/

This was an update from Ron Davis on PR in Dec 2019

The full statement about the work can be found here.
https://forums.phoenixrising.me/threads/nanoneedle-update-finding-whats-in-the-blood.78592/

I assume it didn't get accepted for NIH funding as no news on the application since then. With NIH funding Dr. Esfandyarpour would have very good motivation to assign students to work on it and progress could be accelerated. I have no idea if anybody is assigned to do the work described although it does seem from the update that someone is working on it. Maybe the application can be resubmitted?

This is Dr. Esfandyarpour's bio at UCI Engineering school for those interested.
https://engineering.uci.edu/users/rahim-esfandyarpour

This is a description of his research group. I see no pictures of the nanoneedle, and no mention of it as a specific project. Biggest emphasis is on wearable sensors for health.......
https://faculty.sites.uci.edu/esfandyarpourlab/

There is/was an opening in his group which is for a post doc to work on Organ-on-chip work which is a joint project with Stanford. It is not for nanoneedle.
https://www.linkedin.com/posts/rahi...tdoc-opening-ugcPost-6631684996530868224-y4KB

And there was another Phd student advert 5 months ago, for a position starting in the fall 2020. Perhaps this will include nanoneedle work?
https://www.linkedin.com/posts/rahi...ing-to-uci-activity-6602064237529567232-lpMv/
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Thanks Wigglethemouse. So, basically, the late January news is all we can be accurately sure of at this point. Is this correct? Or perhaps there is more news and we don't really know.....I'm surprised that if NIH didn't grant cash that we would not have heard...this sort of news usually get posted somewhere. All the patients that I know in the severe category are suffering added distress and renewed insomnia because they realise that Covid has turned everything upside down, and they are worried/frightened that ME advancements might be stalled even if researchers are trying their hardest to carry on.
 
Perrier said:
So, basically, the late January news is all we can be accurately sure of at this point. Is this correct?
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The last new NIH grant approvals for ME in NIH reporter system appeared in January. Of the top of my head Leonnard Jason R01 to extend his study of post IM, and R21 for Abdullah

Okay, here are the details
MAINTENANCE AND INCIDENCE OF ME/CFS FOLLOWING MONO (Jason)
Budget Start Date: 1-JAN-2020 R01
https://projectreporter.nih.gov/project_info_description.cfm?aid=9886879&icde=31258613

APPLICATION OF LIPIDOMICS TO IDENTIFY BIOMARKERS OF IMMUNE AND MITOCHONDRIAL DISTURBANCES IN CHRONIC FATIGUE SYNDROME (ABDULLAH).
Budget Start Date: 1-DEC-2019 R21
https://projectreporter.nih.gov/project_info_details.cfm?aid=9841376&icde=31258613
 
Merged thread

The Robert G. Fenley Writing Awards: News Releases – Silver goes to “Biomarker for Chronic Fatigue Syndrome Identified” By Hanae Armitage Stanford

“Biomarker for Chronic Fatigue Syndrome Identified”
By Hanae Armitage
Stanford University School of Medicine
“People suffering from a debilitating and often discounted disease known as chronic fatigue syndrome may soon have something they’ve been seeking for decades: scientific proof of their ailment. Researchers at the Stanford University School of Medicine have created a blood test that can flag the disease, which currently lacks a standard, reliable diagnostic test. ‘Too often, this disease is categorized as imaginary,’ said Ron Davis, PhD, professor of biochemistry and of genetics. … The test, which is still in a pilot phase, is based on how a person’s immune cells respond to stress. With blood samples from 40 people — 20 with chronic fatigue syndrome and 20 without — the test yielded precise results, accurately flagging all chronic fatigue syndrome patients and none of the healthy individuals.”

Scientists led by Ron Davis, PhD, a professor of biochemistry and genetics, developed the first-ever diagnostic blood test for the notoriously mysterious disease myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The test, devised by Dr. Davis and his team, harnessed something called a nanoelectronic assay, which works to assess the stress response of immune cells. The test showed that blood samples from patients with ME/CFS responded in a drastically different manner when compared with immune cells taken from healthy individuals. It’s also possible that the nanoelectronic assay could be used to test the efficacy of potential ME/CFS drugs, but further research will need to confirm this application.

What was the biggest challenge in writing about this topic?
I needed to balance the excitement of this new diagnostic test with the fact that the study size was relatively small. While it’s an important development, I wanted to be sure I wasn’t overstating the research findings.

What was the most impactful part of your award-winning entry?
This work provides the first method to diagnose ME/CFS with scientific evidence, a huge step for ME/CFS patients who often have been ignored or dismissed.
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https://www.aamc.org/professional-d...-g-fenley-writing-awards-news-releases-silver
 
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This is great news. Okay, it is still in a pilot phase, but:

"With blood samples from 40 people — 20 with chronic fatigue syndrome and 20 without — the test yielded precise results, accurately flagging all chronic fatigue syndrome patients and none of the healthy individuals"

The results could not have had a better starting point than this.
 
The test, which is still in a pilot phase, is based on how a person’s immune cells respond to stress. With blood samples from 40 people — 20 with chronic fatigue syndrome and 20 without — the test yielded precise results, accurately flagging all chronic fatigue syndrome patients and none of the healthy individuals.”
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  1. I initially found myself wondering how valuable is this, unless we can be confident it discriminates between ME/CFS and other serious illnesses it might be confused with? To be a true biomarker it would have to uniquely and unambiguously identify ME/CFS. However ...
  2. Given ME/CFS is currently diagnosed by excluding other serious illnesses it might be confused with, then if despite this a patient also shows clear biomedical abnormality, then - as Sherlock might have said - what is left must be ME/CFS. The biomarker would not have to discriminate, because the exclusion diagnosis has already done so. No matter how improbable the GET-brigade might find that truth to be.
  3. The patient group who might fall down the cracks with this, could be those with a serious illness that can be confused with ME/CFS, but who go on to develop ME/CFS later on. If the biomarker did not uniquely single out ME/CFS, the patient's symptoms might severely worsen but be assumed simply a deterioration of the pre-existing condition.
  4. So a biomarker only reliably discriminating ME/CFS from healthy people would nonetheless be a huge step forward, combined with existing diagnostic methods, confirming a real physical illness. This would help a significant majority of pwME, whose first diagnosis is that of ME/CFS.
  5. A biomarker unique to ME/CFS would be the icing on the cake. People already suffering from one of the other illnesses, could then get a clear diagnosis if they then later developed ME/CFS.
  6. Most importantly of course, this biomarker would have to not show up in people with mental illness such as depression etc. who do not also suffer from ME/CFS, which some psychiatrists seek to attribute ME/CFS to. If we could have a biomarker that truly did single out ME/CFS uniquely and unambiguously, then it might even transpire that some people diagnosed solely with depression etc., might in fact prove to have both ME/CFS and depression.
 
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Merged thread

Difference Between the Nanoneedle and Other Impedance Analyzers?

What’s the difference between the nanoneedle and off-the-shelf impedance analyzers? Can off-the-shelf counterparts separate ME/CFS PBMCs with ME/CFS plasma from those with healthy plasma? And while utilizing the salt-stress test?

Here’s a summary of how 2 impedance analyzers work:
  • Nanoneedle: “The assay detects any impedance modulation due to the presence and/or interactions of biomolecules of interest at the active sensing region of the sensors [1].”
  • xCELLigence RTCA: “Changes in morphology, adherence and cell numbers lead to impedance shifts reflected as cell index (CI) alterations which are dynamically recorded using the instrument [2].”
I’m not quite sure how similar these are. Maybe cell numbers and adherence mean the same as “presence and/or interactions of biomolecules,” which the nanoneedle uses to measure impedance. It’s also of interest that the xCELLigence system can measure changes in morphology. Maybe this could be used to replicate Prusty’s findings [3] about changes in mitochondrial morphology.

So, could this be a viable avenue of searching for the “something in the blood?”
 
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This is something I've wondered about. I think one of the things with microfluidic devices is that they can use very small amounts of a sample e.g. small droplets so that could have a difference. Also there could be something around the accuracy of impedance measurements - I don't know about this but could using something at a very small scale (i.e. very short distances) make it easier to measure small impedance changes?
 
I have never really understood what the nano needle is trying to measure. At one point I thought I could see what it would do but I have forgotten. It uses very small electrodes very close together so presumably it is measuring impedance across individual cells. That would normally involve a microscope and putting electrodes in a specific place in relation to a cell but as far as I can see it is done in troughs or wells without visualising cells.

The result will surely depend entirely on what size the instrument is, how far apart the electrodes are, and what sort of cell preparation is used. To talk of measuring impedance for cells is a bit like measuring impedance for a radio - it will depend entirely on where in the radio you attach your test wires.
 
xCELLigence RTCA S16 Real Time Cell Analyzer – 16 well
https://www.aceabio.com/products/rtca-s16/

A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
https://www.pnas.org/content/116/21/10250

The Stanford device has thousands of sensors (needles) but I can't tell how many sensors the xCELLigence devices have, other than "a set of gold microelectrodes" per well. Whether the Stanford device has many more sensors than the xCELLigence I don't know.
 
Jonathan Edwards said:
It uses very small electrodes very close together so presumably it is measuring impedance across individual cells. That would normally involve a microscope and putting electrodes in a specific place in relation to a cell but as far as I can see it is done in troughs or wells without visualising cells.
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Could it be that by having a large number of closely spaced sensors, then the technology may be relying on statistical probability of enough cells being suitably placed, without needing to micro-manoeuvre sensors onto individual cells?
 
Barry said:
Could it be that by having a large number of closely spaced sensors, then the technology may be relying on statistical probability of enough cells being suitably placed, without needing to micro-manoeuvre sensors onto individual cells?
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I guess that is the hope. But if you were checking batteries for voltage you would want to make sure your electrodes are positioned at either end, not just touching the batteries. I would expect cells to be similar. The relevance of any impedance measurement will depend on what it is impedance across.
 
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