MEAction 2021 MECFS researchers video with R Davis,Prusty

[Jaybee00]

 

[Milo]

I’d be thankful for anyone writing the salient points of this presentation

 

[Lisa108]

I've done a transcript of Dr. Bhupesh Prusty's interview, using the subtitles from Youtube.

Main take-aways for me were that he received two grants for these two projects:

1. A two-year project, funded by ME Research UK with ~270,000 GBP, with a focus on finding "autoantibodies that can target mitochondria for dysfunction"

2. A three-year project, funded by Amar Foundation (US) with 900,000 US$, with a focus on a "unique experimental approach" to "understand long-covid and the relationship of long-covid with ME/CFS"

According to Dr. Prusty, science is "on the right path" and he suspects some exciting developments in the next 3-5 years.

 

[5vforest]

Thanks so much for the transcription, Lisa.

Prusty seems like a very nice, genuine guy and it's great that he is getting what appears to be sizable funding for his research.

It is also nice, I have to say, to see him give an estimation of progress without falling into the "right around the corner" trap. Like, I'm not happy to hear that he isn't on the verge of some imminent breakthrough, but at least I get the sense that he is giving his honest opinion.

 

[Hutan]

18.40 Ron Davis and Janet Dafoe

20.10 Abilify - Ron is convinced that Abilify helps Whitney. OMF is putting a lot of effort into investigating Abilify and dopamine pathways. They are working with scientists and a person who set up a company.

(It wasn't clear to me if the company is Labcorp, or the person is helping to get Labcorp to set up the required testing.)​

Patients will send samples to Labcorp (for diagnosis?). This is where their new effort is, and Ron seems very confident. He thinks it is related to decreased mitochondrial function, that it is a metabolism problem.

23.15 ME/CFS looks a lot like a persistent infection. OMF have already looked for infections, Lipkin has looked for infections - no one has found anything yet. They will look further - DNA or RNA from organisms - viruses, parasites, fungi and bacteria.

24.30 Tryptophan trap Ron says that the community have got confused, thinking that the tryptophan is in the serum, but it's actually the levels that are made in the immune cells that matter. In an infection, the tryptophan is released from the albumin which is then broken down to kynurunine. The enzyme that breaks down the tryptophan is IDO1, but if the level of tryptophan is too high, IDO1 doesn't work. In most people, they have another enzyme, IDO2, that works at high levels of tryptophan. But, if there is a mutation in IDO2 that makes it dysfunctional, high levels of tryptophan make a metabolic trap - there isn't a way to break down the tryptophan. Janet says that 70 patients have been tested for the IDO2 mutation and all but one (who is an 'unusual case') has the mutation.

(Has this been replicated by any other researcher? Surely it wouldn't be so hard to check this finding in other patient populations, and surely that is important to do? If it could be replicated, that would do a great deal for OMF's credibility.
There's an edit straight after Janet talks about the 70 patients, and suddenly the presenter is laughing and Ron is talking about tryptophan in yeast cells. So Ron doesn't confirm the finding of the mutation in all patients tested so far.)​

There was some discussion about yeast cells that have been modified to have a functional human IDO1 and no other way of producing tryptophan, being used to screen drugs.
Ron thinks the tryptophan trap is the primary cause of ME/CFS. He thinks a drug fixing the trap could cure patients overnight.

33.40 Ron is asked what he would say to other researchers. Ron says that researchers should focus their efforts on what helps the patients, and not on publication.

(But surely if OMF paid for a genetic study of a well characterised cohort of ME/CFS patients, if it showed that there is a mutation with IDO2, then lots of researchers could turn their minds to fixing it?)​

Janet says that they would also say to UK researchers to stop spending money on unhelpful treatments like the Lightning Process, CBT, or GET. And for scientists to tell UK clinicians to try saline drips or Abilify or other treatments for symptoms.

36.30 Impact on carers. Lack of knowledge of ME/CFS in the medical profession. Great burden on the family. It's hard when taking care of your loved one actually hurts them.

43.00 Message for the community. Ron continues to try to figure ME/CFS out and bring in other scientists. OMF is working with Mark Davis, an immunologist. Mark got the grant and OMF is providing the patients, and they are learning a lot about the immune system - unique cells and autoantibodies. Data that is collected is made available publicly for others to use. Janet says that they want everyone to have hope. Janet says she tries to 'instil hope by giving out information, and sometimes she calls people up just to help them out with the things she does know about'. She does have hope, even though it is slow. She suggests patients work on having gratitude for the things that we do have in our life that we appreciate, and be in the moment and find pieces of joy and try not to focus on the future or the past. She mentions Whitney's recent article in the Healthcare Journal.
Ron says that patients worry that they don't really have a disease, and shame means that the disease isn't mentioned (but there are very clear biological anomalies).

Ron mentions PANS - disease in children caused by a strep infection. He thinks it's very similar to ME/CFS. There's a PANS clinic in Stanford, Jennifer Frankovitch runs it. She says that if she can get the patients within a year, she can fix them with high steroid concentrations. Which makes Ron concerned that there is just a short time for fixing people with Long Covid. Janet says to people with Long Covid 'rest, don't go over your energy limits, don't listen to any doctor that prescribes energy, and it's not depression or anxiety'.

51.50 End of the section with Ron and Janet

 

[Andy]

and he suspects some exciting developments in the next 3-5 years.

And hoe long ago did Lipkin say pretty much the same thing?

Ron says that researchers should focus their efforts on what helps the patients, and not on publication.

The two things are not necessarily mutually exclusive. And perhaps this view makes the funders reluctant to give Ron any funding, if they can't be confident he will publish anything why give him him public money?

(But surely if OMF paid for a genetic study of a well characterised cohort of ME/CFS patients, if it showed that there is a mutation with IDO2, then lots of researchers could turn their minds to fixing it?)

Exactly. If OMF's efforts and results remain outside of the usual way of distributing scientific information then that impedes the global effort to figure out ME.

ETA: deleted unnecessary word.

 

[Solstice]

And hoe long ago did Lipkin say pretty much the same thing?

The important caveat that Lipkin included in his statement was that enough funding was provided. This still doesn't seem to be the case.

 

[Milo]

33.40 Ron is asked what he would say to other researchers. Ron says that researchers should focus their efforts on what helps the patients, and not on publication.

If nothing is published, most drugs cannot be prescribed off-label here in Canada. No publication, no evidence the drug works, drug is not covered.

if there is no publication, a particular test would not be covered, such as a diagnostic test.

re: doctor focusing on making patients better, there is an issue with liability in prescribing off-label. Then family doctors will usually not venture deep down into cell biology.

i worry that Dr Davis lacks understanding of how the health care systems work. Most patients do not have access to the privileges that they have from workplace, drs, connections, etc.

edit to add: no publication also means our disease remains underground, underfunded and left behind

 

[Trish]

No publication, if that really is policy, is also likely to put off good researchers, especially early career researchers, since their careers depend on publication records unless they are tenured, which many aren't. I haven't watched the video, but I remember similar comments from Ron Davis in previous talks. I suspect it's more a case of ordering his own priorities for use of his own limited time, rather than OMF research policy.

 

[Andy]

I suspect it's more a case of ordering his own priorities for use of his own limited time, rather than OMF research policy.

Then, in my opinion, he should be making that clear, because otherwise people will understandably take it as OMF research policy, considering who he is.

 

[Ariel]

I find this idea of not publishing your research - especially if you say you have significant-sounding findings - to be impractical and unscientific. It is self-sabotage, really. I am sure it's just a question of time priorities, but OMF needs to reconsider its strategy both in terms of the practical matter of advancing research understanding, and the kinds of comments made in public which can easily be used against the effort more broadly.

It's also no good creating an evidence base for treatment if you don't publish it. I mean...?

 

[Mij]

He's offering what he has, but making it appear that it’s more than what it is. I would rather hear that they're making progress in treating symptoms than getting people's hopes up and continue to say "cure". I feel it diminishes the seriousness of this illness.

 

[MeSci]

And hoe long ago did Lipkin say pretty much the same thing?

From the vast amount of research I've read over the years (unable to read much now) it's pretty standard to say that the scientists expect significant results in 5 years, presumably because it ensures ongoing funding. Often the science is rubbish. This doesn't sound particularly rubbishy though.

 

[Jaybee00]

not publishing your research - especially if you say you have significant-sounding findings - to be impractical and unscientific.

He is not saying don't publish your research. He is saying the effort should be on finding cures not generating publications. Modern academia emphasizes publishing whether or not the article/research is important. If the researcher is overly concerned with generating publications for tenure and promotion (which is time-consuming), then the less time that they will spend on the actual research itself.

 

[Helen]

24.30 Tryptophan trap Ron says that the community have got confused, thinking that the tryptophan is in the serum, but it's actually the levels that are made in the immune cells that matter. In an infection, the tryptophan is released from the albumin which is then broken down to kynurunine. The enzyme that breaks down the tryptophan is IDO1, but if the level of tryptophan is too high, IDO1 doesn't work. In most people, they have another enzyme, IDO2, that works at high levels of tryptophan. But, if there is a mutation in IDO2 that makes it dysfunctional, high levels of tryptophan make a metabolic trap - there isn't a way to break down the tryptophan. Janet says that 70 patients have been tested for the IDO2 mutation and all but one (who is an 'unusual case') has the mutation.

Maybe the results from 23andme tests could be useful. I just checked my test results from about 10 years ago, and there were several results from different IDO2 SNPs. At that time many of us had the test, so if we could get the actual
rs number-s, and they were analyzed in the test, we could have quite a few results in a short time. Just an idea.

 

[Lisa108]

Transcript of the second part of the video (Interview with Ron Davis & Janet Dafoe)

ETA the transcript of the last interview with Prof. Sarah Tyson

 

[J.G]

He is not saying don't publish your research. He is saying the effort should be on finding cures not generating publications. Modern academia emphasizes publishing whether or not the article/research is important. If the researcher is overly concerned with generating publications for tenure and promotion (which is time-consuming), then the less time that they will spend on the actual research itself.

Quite right. "Publish or perish" is a common turn of phrase in academia. Gotta meet your quota of peer-reviewed published papers or risk losing your job! These pressures have trickle-down effects from research risk adversity (negative results are hard to get published) to pro forma studies designed just to generate a bunch of data that can be transformed into fast papers. The science suffers, and much time (and money) is squandered. It's how the system is set up, unfortunately.

 

[Hutan]

He is not saying don't publish your research. He is saying the effort should be on finding cures not generating publications. Modern academia emphasizes publishing whether or not the article/research is important. If the researcher is overly concerned with generating publications for tenure and promotion (which is time-consuming), then the less time that they will spend on the actual research itself.

I can see what you are saying, I agree with it even. But what we are seeing from OMF, and also from the Stanford clinical team that has been promoting Abilify, is research that isn't robust enough to tell people outside of the Stanford bubble if there is really something worth pursuing. We just have anecdotal evidence that Abilify helped Whitney. The unblinded Abilify study from the clinical team did nothing to bring clarity.

I get that Ron feels compelled to move swiftly to find something to cure his son, and that creates an incentive to work differently. But, a robust finding (regarding Abilify and/or the IDO2 mutation prevalence) would either rapidly bring more researchers and more funders on board and probably make progress quicker, or make it clear that the community's research funds would be better targeted elsewhere. Neither study would be terribly expensive.

I'm sure that we aren't getting the whole story and I hope that things are more solid than they seem from here. A paper with a real finding would do a lot to establish OMF's credibility. It need not take much of Ron's time - the OMF board could just use some of their funding to get an independent research team to do a study. I suspect that with OMF's social media reach, they could probably even fund such a study largely by crowd funding.

 

[Ariel]

A paper with a real finding would do a lot to establish OMF's credibility. It need not take much of Ron's time - the OMF board could just use some of their funding to get an independent research team to do a study. I suspect that with OMF's social media reach, they could probably even fund such a study largely by crowd funding.

I could not agree more, and I hope this is done as soon as possible. It does not seem that difficult compared to the other research and funding challenges. Something on this IDO2 mutation would be really interesting and as you say would spur interest from others. This approach seems to silo the research unnecessarily, potentially slowing things down whereas the goal is presumably to speed it up by not prioritising writing up research. Targeted papers - not pointless, but informative, transparent, and designed to catalyze the process - seem worth doing.

 

[JES]

They seem vested in the IDO2 metabolic trap hypothesis, maybe a little too much in my view. I still haven't learned why they decided to pick that particular gene and mutation out of the tens of thousands of other genes. Even if they only consider genes that could create a bistable system and metabolic trap, Phair has already mentioned there are several other candidates.

The other question is how it ties into the Abilify improvements, which seems hard to understand. If they believe that the metabolic trap is the cause of the disease and that Abilify improves patients, then you'd think Abilify would affect kynurenine or tryptophan pathways in some way, but everything we hear is that it primarily affects dopamine.

I also think they should publish more. Actually, this paper from Moreau et al. who collaborate with OMF is in the 99th percentile of all articles of similar age according to metrics, so clearly such articles can have a big impact.