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

[Jonathan Edwards]

If you test samples using the nano-needle and e.g. also:

• measure Oxygen Consumption [Karl Morten]; and/or
• measure the surface area/morphology [Bhupesh Prusty]; and/or
• remove the exosomes (filter plasma/serum) and re-test.

Then presumably you can work out whether the nano-needle gives false positives/negatives. If it's the method least likely to give false negatives/positives, is reliable (i.e. can be used in hospital laboratories etc.) and relatively cheap, then what's the problem?

The problem for me and Jo Cambridge is that much as we would love to do these things we cannot work out what was done in the first place.

 

[anciendaze]

There are four things important when filing for a patent that may be relevant here: novelty, utility, priority and non-obviousness (if that is a word.) I think the role of this short paper in establishing the first three is clear, if it does what they say. The last factor is that the device should not be obvious "to someone skilled in the art".

Publishing a short paper like this to establish those factors is a standard move. Finding that you cannot simply step down to your lab. and gin up a comparable device in a few minutes, based on a limited description, is a familiar experience in the patent world. If it were that easy, the patent would likely be worthless. I'm betting there will be a series of papers, and the fact that just having the idea is not enough to lead to a working device will support the last factor above. This will slow the science rather than stop it. In the end there will be a fully-described device with a sound legal basis for a patent. After all, that is what the word patent means, you must make it clear to others what you are doing or you don't have a patent.

(I wish that this ideal were true of all patents, and I've seen some that are simply aimed at employing attorneys.)

You can also encounter surprises in trying to reproduce an invention so described. In one case where we thought we had figured out the method behind a claim, we had a new invention. Unfortunately, the expense and effort needed to establish a contested patent claim were deemed too much, and I didn't gain anything as a result.

 

[arewenearlythereyet]

I have to say this. We are only talking about a preliminary study but there is a scientific convention that says if you publish, you invite others to try and reproduce or disprove your work. This is the principle of scientific advancement and pretty fundamental. It’s not about patent law or protecting trade secrets. I’m not sure but there are no commercial stakeholders here other than the government grant and charitable donations. It’s nit private product development?

You shouldn’t have to seek permission to reproduce a scientific paper by asking for key bits of information....although it’s always good to collaborate.

I realise this is very different from commercial trade secrets so I just wanted to make the point that something is a bit odd here if JE can’t work it out from the paper.

 

[arewenearlythereyet]

I should also say that I have worked in both government grant funded research and private funded research and commercial product development. They are all a bit different from one another.

 

[rvallee]

But if nobody can replicate the work the science does not move forward and the patients remain at square one. I thought that Davis was motivated by trying to get his son better. The way to do that would be to publish stuff that other scientists can understand.

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.

 

[rvallee]

you invite others to try and reproduce or disprove your work

Alternatively, there is the "huff and puff" psychosocial approach where you are so massively pissed off about your ideological nonsense being disproved that you fail to express cautious optimism about the most significant potential breakthrough in decades of research, one that could lead to a massive improvement in quality of life for millions.

Clearly, not everyone who goes into medicine is there to help people. They are showing themselves in broad daylight over this in the "fuck those lazy fucks" school of thought.

 

[anciendaze]

Since the subject of trade secrets has been introduced above, I will say that we should be thankful Ron Davis and Stanford are not treating this as a trade secret. Patents expire, but trade secrets can last forever, unless they are breached, in which case the holder of a trade secret has very limited recourse.

Bizarre things take place in the world of patents, but the subject of trade secrets is full of smoke and mirrors. I've avoided some work simply because it would have required an NDA giving someone else control over something held in my mind. I've also signed some that seemed less restrictive. NDAs can be used for unsavory purposes that approach mafia oaths.

 

[wigglethemouse]

Some food for thought.

It seems 2019 BGA packaging substrates use 12um line / 12um space technology on flip chip BGA packages for mass production. Here are some images. I imagine something like this would be good to experiment with.

This 10um image is about the diameter of a cell. Two cells touching could be detected, or maybe one large PBMC cell. Maybe you wouldn't need a micro channel. I just don't understand how diluted the cells are in the salt and plasma and how often two cells would touch allowing a measurement.

If the cells sink in the sample maybe you could use flip-chip bumps as the circuit contacts to measure impedance, assuming cells would clump in the valleys of the bumps.

Link : https://www.toppan.co.jp/electronics/english/semicon/package/fc-bga/

A quick and dirty experiment just to see what happens could use inter-digitated circuit boards. Now if you could find a way to get the cells to clump on the traces.... build a little moat around them?

Source : https://www.ossila.com/products/interdigitated-ito-ofet-substrates
20 for $112

 

[arewenearlythereyet]

Since the subject of trade secrets has been introduced above, I will say that we should be thankful Ron Davis and Stanford are not treating this as a trade secret. Patents expire, but trade secrets can last forever, unless they are breached, in which case the holder of a trade secret has very limited recourse.

Bizarre things take place in the world of patents, but the subject of trade secrets is full of smoke and mirrors. I've avoided some work simply because it would have required an NDA giving someone else control over something held in my mind. I've also signed some that seemed less restrictive. NDAs can be used for unsavory purposes that approach mafia oaths.

Yes I’ve been involved in patents and nda’s having worked in a research institute.

To be honest NDA’s are pretty standard for commercial product development for third parties. But normally patents are something you sort out in parallel with the research and doesn’t affect the content of what you publish. It certainly doesn’t stop you from publishing research correctly (non secretively) ....well it always used to work that way. Most of the patent stuff I was involved in was for private American funding stakeholders rather than government research though. Perhaps there is a commercial stakeholder rather than this being what I thought it was (government funded with a bit of non stakeholder charitable donation).

 

[wigglethemouse]

And here is a MEMS interdigitated sensor with fingers 5um apart. Cells more likely to be measured at these geometries

source : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855898/

 

[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"

 

[anciendaze]

Yes I’ve been involved in patents and nda’s having worked in a research institute.

To be honest NDA’s are pretty standard for commercial product development for third parties. But normally patents are something you sort out in parallel with the research and doesn’t affect the content of what you publish. It certainly doesn’t stop you from publishing research correctly (non secretively) ....well it always used to work that way. Most of the patent stuff I was involved in was for private American funding stakeholders rather than government research though. Perhaps there is a commercial stakeholder rather than this being what I thought it was (government funded with a bit of non stakeholder charitable donation).

I tried to say that I've signed NDAs that seemed reasonable, but I've rejected some that amounted to "yellow-dog contracts", if not fealty. If you are dealing with reasonable and decent people, these agreements are likely to be reasonable. If you are dealing with unreasonable and litigious people, you are playing poker with deuces wild.

If you check on silicon valley corporations that were started by researchers from Stanford, you will find some pretty substantial ones, and at least one which resulted in disaster and serious charges of misconduct. Hewlett Packard would be plenty for most universities to claim to have spawned, and Intel was founded by graduates of Caltech and MIT, not Stanford, but leaders of the team that designed the first microprocessors came from Stanford. I'm not even sure how you value the resulting intellectual property.

The problem is not merely having some commercial interests, (you'd be surprised at how hard it is to avoid that,) the problem is the sheer scale of financial interests. With the kind of money resulting from these startups, you are definitely into the range where I posit that otherwise normal people behave like psychotics. When you have parts of government with similar budgets you also get bizarre political behavior which also causes one to question sanity. If you are looking for altruistic angels, or even decent humans, handling such money you are likely to be disappointed. What Lord Acton said about power also applies to the flowing power of money.

People are a problem. People together with large amounts of money are a wicked problem. All our current solutions are temporary expedients requiring a great deal of effort to maintain them, and to fix them when they break down.

 

[Sean]

Another reason could be that the closer together the electrodes, the higher the current, so background noise is much less. These are very tricky measurements and high impedance's are very difficult to measure in labs full of 60Hz background noise (paper describes needing faradic cage to minimise electrical lab noise).

I put money on this one.

 

[wigglethemouse]

The problem for me and Jo Cambridge is that much as we would love to do these things we cannot work out what was done in the first place.

@Jonathan Edwards Taking @FMMM1 idea further what if you did the Karl Morten oxygen consumption experiment but with no impedance measurement and PBMC's instead of muscle cells. We know the ratio's of plasma, PBMC and salt solution. Start with PBMC + plasma and get a baseline oxygen consumption, and then add the salt and monitor to see how the oxygen consumption changes. Record the max differential from baseline. Maybe that shows something about the "stress" of the salt that could also be a biomarker?

Would that be a feasible quick experiment (I know nothing of biology)?

 

[wigglethemouse]

For reference here is the slide of the Karl Morten muscle cell plasma swap experiment

 

[roller*]

this curve looks like the signal one... going much down initially

the davis-curve (salt) with the signal then explodes, while this morten-plasma (oxygen) from 1:75h stays the same

 

[Jonathan Edwards]

@Jonathan Edwards Taking @FMMM1 idea further what if you did the Karl Morten oxygen consumption experiment but with no impedance measurement and PBMC's instead of muscle cells.

Yes, that is what Jo Cambridge suggested.

 

[Inara]

After all, that is what the word patent means, you must make it clear to others what you are doing or you don't have a patent.

The art is, though, to get a patent without explaining in detail how to do it. A patent is not a step-by-step how-to, it needs to be understood by an "expert" of the field; what that is is quite interpretable. After all, the office will grant a patent and you have to enforce it before court; the office wants money, too.

 

[Inara]

These could be the lead author's published patents, although the first name is different.

Why could be? If the first name is different, it's not the same person?

 

[arewenearlythereyet]

The art is, though, to get a patent without explaining in detail how to do it. A patent is not a step-by-step how-to, it needs to be understood by an "expert" of the field; what that is is quite interpretable. After all, the office will grant a patent and you have to enforce it before court; the office wants money, too.

Which is why patents aren’t the same as the scientific paper that you publish. It’s also why the timing of when you publish the paper and lodge the patent is important.

Having a patent does not proclude you publishing a detailed account of what you have done. You just need to get your timings right and be organised. It’s rare that fudging a scientific paper ever leads to a watertight patent after the fact ...if they were concerned they would lodge the patent before publishing? Lodged patents are in the public domain I believe so this can be checked. Of course some things are not patentable for other reasons.

If information is being deliberately excluded as others seem to be suggesting this begs a number of questions.

Who is the commercial stakeholder that is driving this when the funding comes from a charity supposedly managing mainly patient donations and the government? Neither of which should have a commercial stake in the development of future products for profit.

I think whether this is deliberately obscure for commercial gain is highly debatable, especially as the OMF and Ron has approached the projects in a collaborative way.

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.