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

[anciendaze]

...
I personally think it’s unlikely given the funding. More likely it’s just a rushed publication that could have been written better in places or there are plans to publish a second more detailed paper quite soon.

Even if this is complete happenstance it could serve to establish the elements of a patent I described, so university attorneys would not object. Had the paper made replication too easy they might have.

I really hope you are right about a second paper with more detail already on the way. I think this likely, even if there is more to the story behind the scenes. Ron Davis has the best of motives, but he is one individual who must deal with an entire university/industrial ecosystem. Getting funding is a constant concern, and the pennies we patients can contribute are unlikely to go far.

Painful experience does not stop me from thinking about attempts to profit from government and charitable funding. We've all had a number of surprises about charitable foundations just this year. Also, recall what happened yesterday concerning a medical treatment option that was worth billions. Could behavior get more corrupt?

Good and honorable people have to be aware there are others around with worse motives. If they don't protect themselves, they are likely to end up in court through no fault of their own.

 

[Kalliope]

 

[wigglethemouse]

Looks like Nanoneedle technology is still being developed by Ron Davis's teams at Stanford for other purposes. This is a current NIH grant for a cancer project. Title sounds very futuristic.

NANONEEDLE MICROROBOTS FOR SINGLE CANCER CELL MANIPULATION AND GENOME EDITING

The proposed research will develop a new nanoneedle-based 3D (x,y,z) actuation technology for manipulating and analyzing single cells on a massively parallel scale. The long term objective of this project is to develop a platform that will increase the throughput of single-cell manipulation and analysis by at least 1000-fold while significantly decreasing costs.

 

[rvallee]

Perhaps there is a commercial stakeholder

That's Stanford. Private universities have a commercial mandate in the US. They think very differently, it isn't just academic, they're in the business of making money first, a good education is just the product they sell to achieve that but income comes first in their priorities.

 

[rvallee]

Looks like Nanoneedle technology is still being developed by Ron Davis's teams at Stanford for other purposes. This is a current NIH grant for a cancer project. Title sounds very futuristic.

NANONEEDLE MICROROBOTS FOR SINGLE CANCER CELL MANIPULATION AND GENOME EDITING

$314K. That's peanuts compared to the private funding from patients.

wE're HeLPiNg

 

[wigglethemouse]

The paper lists NIH grant number R01 HG000205. The grant ran from 1994 and ended in 2016 (coincidentally after Ron complained that NIH wouldn't fund his ME/CFS work). It was a massive grant ($5MM in 2016).

REVOLUTIONIZING BIOMEDICAL AND CLINICAL RESEARCH THROUGH INNOVATIVE TECHNOLOGY
https://projectreporter.nih.gov/project_info_history.cfm?aid=9130903&icde=44461818

According to Twitter above this funded the earlier nanoneedle work for other applications.

The grant funded work that resulted in a lot of papers and patents. NIH lists 2 nanoneedle patents resulting from this grant.
https://projectreporter.nih.gov/project_info_results.cfm?sp=1&aid=9130903&icde=44461818

 

[wigglethemouse]

These could be the lead author's published patents, although the first name is different. At least one of them is assigned to Stanford

PAT. NO.
Title
1 9,926,596

Systems and methods for genetic and biological analysis
2 9,399,217

Chamber free nanoreactor system
3 9,187,783

Systems and methods for automated reusable parallel biological reactions
4 9,184,099

Biosensor devices, systems and methods therefor
5 8,696,989

Calorimeter sensor
6 8,585,973

Nano-sensor array
Source : http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-adv.htm&r=0&f=S&l=50&d=PTXT&Query=AANM/"Esfandyarpour"

I found another patent filed in 2013 and granted in 2016. 9,434,983. This one has images. Would seem to cover most bases. [EDIT: This seems to have tip 212 - the recent ME/CFS paper did not mention these tips, so could be different]
http://patft1.uspto.gov//netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=/netahtml/PTO/srchnum.htm&r=1&f=G&l=50&s1=9434983.PN.&OS=PN/9434983&RS=PN/9434983

PDF View
https://pdfpiw.uspto.gov/.piw?PageNum=0&docid=09434983&IDKey=36A1BC601C6F &HomeUrl=http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1%26Sect2=HITOFF%26d=PALL%26p=1%26u=%252Fnetahtml%252FPTO%252Fsrchnum.htm%26r=1%26f=G%26l=50%26s1=9434983.PN.%26OS=PN/9434983%26RS=PN/9434983

 

[wigglethemouse]

Could this be the relevant patent application - 17 January 2019 [filed July 12, 2018]
http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&co1=AND&d=PG01&s1=Esfandyarpour.IN.&OS=IN/Esfandyarpour&RS=IN/Esfandyarpour

In one embodiment, a method is provided for the manufacture of a nano-sensor array. A base having a sensing region is provided along with a plurality of nano-sensors. Each of the plurality of nano-sensors is formed by: forming a first nanoneedle along a surface of the base, forming a dielectric on the first nanoneedle, and forming a second nanoneedle on the dielectric layer. The first nanoneedle of each sensor has a first end adjacent to the sensing region of the base. The second nanoneedle is separated from the first nanoneedle by the dielectric and has a first end adjacent the first end of the first nanoneedle. The base is provided with a fluidic channel. The plurality of nano-sensors and the fluidic channel are configured and arranged with the first ends proximate the fluidic channel to facilitate sensing of targeted matter in the fluidic channel.

These are the claims of this patent application

1.-3. (canceled)

4. A method for sensing, comprising: (a) providing a sensor array including a plurality of sensors, wherein a sensor of said plurality of sensors includes a first electrode and a second electrode adjacent to a base, wherein said first electrode and said second electrode are separated by a dielectric and include ends that are adjacent to one another, and wherein said first electrode and said second electrode are disposed in different planes relative to a surface of said base; (b) flowing a species through a channel in fluid communication with said ends of said first electrode and said second electrode of said sensor; and (c) using a detection circuit coupled to said sensor to detect a local change in a signal within a sensing region adjacent to said ends of said first electrode and said second electrode, wherein said local change in said signal is indicative of a presence of said species within said sensing region.

5. The method of claim 4, wherein said local change in said signal is a change in local ion concentration.

6. The method of claim 4, wherein said local change in said signal is a change in local impedance.

7. The method of claim 4, wherein said local change in said signal is a change in local conductivity.

8. The method of claim 4, wherein said sensing region is disposed within a double layer of said ends of said first electrode and said second electrode.

9. The method of claim 4, wherein said dielectric varies in thickness such that a portion of said dielectric disposed adjacent to said ends of said first electrode and said second electrode is thinner than another portion of said dielectric disposed away from said end of said first electrode and said second electrode.

10. The method of claim 4, wherein said dielectric further comprises a probe that binds said species.

11. The method of claim 4, wherein said first electrode or said second electrode further comprise a probe that binds said species.

12. The method of claim 4, wherein said sensor further comprises a passivation layer or oxidation layer, and wherein said passivation layer or said oxidation layer reduces a surface area of said first electrode and said second electrode exposed to said species.

13. The method of claim 4, wherein said species is a nucleic acid molecule.

14. A sensing device, comprising: a sensor array including a plurality of sensors, wherein a sensor of said plurality of sensors comprises a first electrode and a second electrode adjacent to a base, wherein said first electrode and said second electrode are separated by a dielectric and includes ends that are adjacent to one another, and wherein said first electrode and said second electrode are in different planes relative to a surface of said base; a channel in fluid communication with said ends of said first electrode and said second electrode, wherein said channel is configured to flow a species; and a detection circuit coupled to said sensor, wherein said detection circuit detects a local change in a signal within a sensing region adjacent to said ends of said first electrode and said second electrode, wherein said local change in said signal is indicative of a presence of said species within said sensing region.

15. The device of claim 14, wherein said local change in said signal is a change in local ion concentration.

16. The device of claim 14, wherein said local change in said signal is a change in local impedance.

17. The device of claim 14, where said local change in said signal is a change in local conductivity.

18. The device of claim 14, wherein said sensing region is disposed within a double layer of said ends of said first electrode and said second electrode.

19. The device of claim 14, wherein said dielectric varies in thickness such that a portion of said dielectric disposed adjacent to said ends of said first electrode and said second electrode is thinner than another portion of said dielectric disposed away from said end of said first electrode and said second electrode.

20. The device of claim 14, wherein said dielectric further comprises a probe that binds to said species.

21. The device of claim 14, wherein said first electrode or said second electrode further comprises a probe that binds to said species.

22. The device of claim 14, wherein said sensor further comprises a passivation layer or oxidation layer, and wherein said passivation layer or said oxidation layer reduces a surface area of said first electrode and said second electrode exposed to said species.

23. The device of claim 14, wherein said species is a nucleic acid molecule.

Rahim has a long list of patents applications - 36 in total. It looks like he uses a different first name for official patent filings, perhaps his official name.
http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=0&f=S&l=50&TERM1=Esfandyarpour,+Hesaam&FIELD1=IN&co1=AND&TERM2=&FIELD2=&d=PG01

1 20190017103 NANO-SENSOR ARRAY
2 20180335401 BIOSENSOR DEVICES, SYSTEMS AND METHODS THEREFOR
3 20180327837 SYSTEMS AND METHODS FOR GENETIC AND BIOLOGICAL ANALYSIS
4 20180282806 SYSTEMS AND METHODS FOR GENETIC AND BIOLOGICAL ANALYSIS
5 20180282805 SYSTEMS AND METHODS FOR GENETIC AND BIOLOGICAL ANALYSIS
6 20180268942 METHODS AND SYSTEMS FOR IDENTIFYING BRAIN DISORDERS
7 20180245150 SYSTEMS AND METHODS FOR GENETIC AND BIOLOGICAL ANALYSIS
8 20180155780 SYSTEMS AND METHODS FOR BIOLOGICAL ANALYSIS
9 20180119215 SYSTEMS AND METHODS FOR DETECTION AND ANALYSIS OF BIOLOGICAL SPECIES
10 20180100190 SYSTEMS AND METHODS FOR NUCLEIC ACID SEQUENCING
11 20180051332 SYSTEMS AND METHODS FOR GENETIC AND BIOLOGICAL ANALYSIS
12 20170268053 PH MEASUREMENT FOR SEQUENCING OF DNA
13 20170096705 MICROFLUIDIC DEVICES, SYSTEMS AND METHODS FOR SAMPLE PREPARATION AND ANALYSIS
14 20170073750 SYSTEMS AND METHODS FOR AUTOMATED REUSABLE PARALLEL BIOLOGICAL REACTIONS
15 20170065977 CHAMBER FREE NANOREACTOR SYSTEM
16 20160340721 NANO-SENSOR ARRAY
17 20160273032 SYSTEMS AND METHODS FOR BIOLOGICAL ANALYSIS AND COMPUTATION
18 20160186252 PH MEASUREMENT FOR SEQUENCING OF DNA
19 20160108469 CHAMBER FREE NANOREACTOR SYSTEM
20 20160077049 BIOSENSOR DEVICES, SYSTEMS AND METHODS THEREFOR
21 20160076097 SYSTEMS AND METHODS FOR AUTOMATED REUSABLE PARALLEL BIOLOGICAL REACTIONS
22 20150376692 SYSTEMS AND METHODS FOR BIOLOGICAL ANALYSIS
23 20150368707 SYSTEMS AND METHODS FOR AUTOMATED REUSABLE PARALLEL BIOLOGICAL REACTIONS
24 20150258544 MICROFLUIDIC DEVICES, SYSTEMS AND METHODS FOR SAMPLE PREPARATION AND ANALYSIS
25 20150148264 SYSTEMS AND METHODS FOR AUTOMATED REUSABLE PARALLEL BIOLOGICAL REACTIONS
26 20140329699 SYSTEMS AND METHODS FOR HIGH EFFICIENCY ELECTRONIC SEQUENCING AND DETECTION
27 20140235457 SYSTEMS AND METHODS FOR GENETIC AND BIOLOGICAL ANALYSIS
28 20140073531 NANO-SENSOR ARRAY
29 20140057339 SYSTEMS AND METHODS FOR GENETIC AND BIOLOGICAL ANALYSIS
30 20140045701 SYTEMS AND METHODS FOR AUTOMATED REUSABLE PARALLEL BIOLOGICAL REACTIONS
31 20130096013 METHODS AND SYSTEMS FOR ELECTRONIC SEQUENCING
32 20130029851 CALORIMETER SENSOR
33 20120302454 NANO-SENSOR ARRAY
34 20120138460 BIOSENSOR DEVICES, SYSTEMS AND METHODS THEREFOR
35 20110171655 PH MEASUREMENT FOR SEQUENCING OF DNA
36 20080166727 Heat and pH Measurement for Sequencing of DNA

 

[Simon M]

Thanks to all those continuing to toil on this thread. Took me awhile to realise how little I understood of the detail of this method and how out of my depth I was.

Though I’m assuming that, regardless of my ignorance of the black box, if the results replicate and hold up using sick controls, the method will still be useful.

Think I’ll leave you to it.

 

[roller*]

would it be interesting to see blood , urine, tissue samples of the same patients after extensive exercise ?


ETA: or perhaps a diving session ?

 

[roller*]

Hypertonic stimulation
High osmotic pressure is able to inflict cell damage and result in the loss of normal physiological function (68).

Intestinal epithelial cells produce inflammatory mediators when exposed to hypertonic fluids, which promotes inflammatory bowel disease (69).

Furthermore, stimulation with hypertonic fluids may cause a series of pathological perturbations in various cells in the lung tissue, including lung epithelial and vascular endothelial cell shrinkage, apoptosis, neutrophil chemotaxis, blood-gas barrier damage, as well as infiltration and secretion of inflammatory cytokines (12–15).

The osmosis-sensitive transcription factor, osmotic response element-binding protein (OREBP) is a member of the Rel transcriptional activators family, which has been previously described (69). OREBP transactivates several genes responsible for cell protection against injury derived from hyperosmosis, such as organic osmolytes (70), heat shock protein 70 (71) and vasopressin-activated urea transporters (72). Although no direct evidence has demonstrated that seawater activates OREBP in ALI/ARDS, it has been reported that multiple OREBP regulators are altered in seawater-drowning-induced ALI/ARDS

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450642/

 

[roller*]

aquaporins breaking down ? too many, too few, something wrong with them or uninteresting ... ?
1.5h was when most of the healthy showed some beep
should be easy to test when healthy blood would react similar after 3-5 hours
the healthy signal looks cut at 2.5h

NaCl, but not urea, destabilized ng-AQP2. The half-life of ng-AQP2 in isotonic conditions was ∼5 h, whereas that in medium supplemented with NaCl was ∼1.5 h. Urea enhanced it compared to isotonic conditions.

These findings indicate that the stability of ng-AQP2 is enhanced by urea, but not NaCl. The degradation of ng-AQP2 was dependent on proteasome and lysosomedegradation pathways. The expression of ng-AQP2 was increased by hyperosmolality. Cell surface biotinylation experiments revealed that hyperosmolality enhanced the apical membrane insertion of ng-AQP2. These results indicate that hyperosmolality plays an important role in the stability, degradation, expression, and targeting of ng-AQP2.

https://www.sciencedirect.com/science/article/pii/S0006291X05024253

Spoiler: curve

 

[FMMM1]

Well, it would be temporary, until Stanford can secure the patents with no possibility of challenge. Once this hurdle is passed they will publish every bit of data. It's annoying but.. them Yankees and their profit motive golden calf.

Yea I remember reading a paper; the research (from memory) was done way before the paper was published. I read the conflicts section and yes they had a patent. So it occurred to me that the reason it took so long to publish the paper was that they delayed until they secured the patent.

 

[FMMM1]

Thanks to all those continuing to toil on this thread. Took me awhile to realise how little I understood of the detail of this method and how out of my depth I was.

Though I’m assuming that, regardless of my ignorance of the black box, if the results replicate and hold up using sick controls, the method will still be useful.

Think I’ll leave you to it.

I'm with @Simon M here i.e. I'm not much interested in the black box bit; however, I'm very interested in whether it is a diagnostic test. Also, when will we see it delivered here in the UK/EU? ME Action are lobbying for the delivery of a diagnostic test
https://www.meaction.net/2019/02/26/announcing-millionsmissing-2019-join-us/

Bear in mind that the NIH study found roughly a third of participants in the "ME/CFS NIH Intramural Study" did not have ME [http://simmaronresearch.com/2019/03/nath-intramural-chronic-fatigue-study/].
So there are a lot of people with a "looks like ME" diagnosis who do not have ME. There may be viable treatments for some of those people; we need clarity.

 

[Trish]

Bear in mind that the NIH study found roughly a third of participants in the "ME/CFS NIH Intramural Study" did not have ME

I'm not clear whether that is correct. For example one person told us of being excluded after the first stage because they were found to have something else in addition to ME/CFS, not instead of ME/CFS. The exclusion was on the basis that that other condition could 'contaminate' the results of some of the tests, and they are keen to have a completely pure sample of people with ME and nothing else. See this post.

 

[FMMM1]

I'm not clear whether that is correct. For example one person told us of being excluded after the first stage because they were found to have something else in addition to ME/CFS, not instead of ME/CFS. The exclusion was on the basis that that other condition could 'contaminate' the results of some of the tests, and they are keen to have a completely pure sample of people with ME and nothing else. See this post.

Thanks @Trish. Ron Davis, speaking recently, said that when you ask an MS doctor whether (MS) patients have fatigue they say "yes but it's caused by MS not ME". I think Ron went on to say that doctors assume that all of your symptoms are caused by one disease. This supports your view i.e. some (unknown proportion) will have 2 diseases; one of which is ME.

Currently, as you are aware/more aware than me, people are diagnosed as having ME on the basis of persistent disabling fatigue and the absence of another known disease - diagnosis by exclusion. The nano-needle (Ron Davis)/morphology (Bhupesh Prusty)/Oxygen Consumption (Karl Morten) "tests" show that the cells return to normal once you filter out the exosomes in the plasma. In 2016, Fluge and Mella proposed that "ME/CFS is caused by immune interference with an unidentified target, potentially a signaling factor" [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]. We now "know"(?) that the signalling is via micro-RNAs (Prusty) in exosomes. So ME is beginning to look like a reversible cellular energy production problem, which is caused by a signalling factor (micro-RNAs) in exosomes.

I'd be very surprised if a very large portion (one third or whatever) of people labelled as having ME:

• do not have ME [i.e. fail a test using one of the above methods - Davis/Prusty/Morten]; or
• have ME and another disease.

Either way those people need an accurate diagnosis; for some at least of these people there are currently treatments - treatments they are now missing out on.

The issue you highlight is relatively easily resolved. The UK Government spent 5 million pounds on the PACE trial. Testing of a large group of people with ME, using one of the above methods [Davis/Prusty/Morten], could be commenced immediately and would cost less than 5 million pounds. That would help to establish the level of ME misdiagnosis - my guess is that is that one third may not be wildly out.

ME Action are lobbying for the delivery of a diagnostic test
https://www.meaction.net/2019/02/26/announcing-millionsmissing-2019-join-us/

@EspeMor @JaimeS

 

[Cheshire]

Posts relating to Simon Wessely have been moved to this thread.

 

[Forbin]

I'm thinking that Gulf War Syndrome (GWS) might be a really important disease to test the nano-needle against.

Nancy Klimas says that the GWS and MECFS are symptomatically indistinguishable. I don't know if that extends to objective measures of dysfunction, like a 2-day CPET, but it might.

Given the similar symptomology, if the nano-needle can distinguish between GWS and MECFS, you could probably rule out that it's detecting common consequences of the diseases, like deconditioning, anxiety, belonging to an online support group, etc.

If it can't distinguish between GWS and MECFS, then it might be detecting a similar underlying process, which would be important if relatively few other diseases showed the same signal.

 

[Kalliope]

I don't think these articles have been shared yet in the thread, so here goes:

Discover Magazine: Scientists Are Closer to Developing a Chronic Fatigue Syndrome Blood Test

STAT News: An experimental test may help confirm cases of chronic fatigue syndrome

 

[rvallee]

I'm thinking that Gulf War Syndrome (GWS) might be a really important disease to test the nano-needle against.

Nancy Klimas says that the GWS and MECFS are symptomatically indistinguishable. I don't know if that extends to objective measures of dysfunction, like a 2-day CPET, but it might.

Given the similar symptomology, if the nano-needle can distinguish between GWS and MECFS, you could probably rule out that it's detecting common consequences of the diseases, like deconditioning, anxiety, belonging to an online support group, etc.

If it can't distinguish between GWS and MECFS, then it might be detecting a similar underlying process, which would be important if relatively few other diseases showed the same signal.

I really don't see the problem with the nanoneedle also identifying other diseases. It could even be a good thing if it brings funding from multiple sources. The pool of diseases that cause this level of exhaustion is tiny so reducing the differential diagnosis search space from hundreds of possible explanations to a handful is still extremely positive, for us and others who could be identified by it.

In most of those cases the disabling nature of extreme levels of exhaustion is downplayed and misunderstood as well, it could bring benefits to a very large population and avance our general understanding of what physiological fatigue is, something that has completely eluded science so far.

Plus the fact that it was not tested against other diseases is entirely down to the fact that funding for a larger study was denied. We're always facing extra obstacles and the gloating of saboteurs about how successful those obstacles are can be ignored as noise. Science is about following evidence where it takes you. It's happening against intense ideological opposition, which is a feat in itself.

The thing about what the signal shows possibly being anxiety or subjective perception of fatigue or whatever is just desperation and misdirection, none of them actually believe that, they're just nervous about their stupid ideology being sent to its rightful place alongside phrenology and the psychosomatic models of peptic ulcers. Fatigue as defined as the subjective perception of tiredness has nothing to do with this, no matter what these fools say.