Folding Forum

Listening to the end-of-year COVID Moonshot presentation https://www.youtube.com/watch?v=fkQwDltGDfU every speaker is explaining what has been done by his/her group - for sure the contributions are fantastic - but in the end for my impression (given the current situation) it stays too much academic. Annette Von Delft is explaining a long route to clinical tests, Frank Von Delft concludes there is no known runway, constitutes problems with project management, missing business models, trouble in funding. Somehow the conclusion is "Ah, we have done a lot and governments should continue that for future pandemics", but conclusions how to save lives now are missing.

While I understand all of that, value the great contributions which have been brought with extreme work hours spent, from my life experience and given the current situation I can't agree with that outcome. I'm now leading a company and that needs to make decisions based on not fully known ground at some times. Back in the early 80s - being a very peaceful person - I went to the army in Germany, became a reserve officer after my experience what the warsaw treaty focused government in eastern Germany aimed at. In such situations you are forced to make decisions not based on long research and with confidence close to 100%, but sometimes at very low confidence levels. However not making a decision could cost more lives than making an only half-way founded decision.

And mankind is in a similar situation now: Worldwide we have about 12000 individuals dying every day, that's about 350 thousand deaths in the month, probably a million more before vaccinations achieve sufficient effect. We have population groups with a risk of death > 20% at the moment they get ill, maybe >50% from the moment the infection gets serious. Unfortunately I'm observing that rather close now. Concluding from the published statistics in the home for older people in the neighbor village from about 100 inhabitants 14 died between December 30 and January 4th. Not much difference in a similar institution in the region right before Christmas.

In that situation - once there is a potentially potent treatment - not making that substance available to people can not be justified. If I have a chance of dying with 50% probability anyhow and if I could take some substance that might help me and has a probability of killing me with less than 10% probability, then I should have that substance available. The risk from what I might die should be my decision and not depend on a two years standard clinical test period. I don't care about pre-clinical and clinical tests if I'm likely to die before those tests are completed. Of course products can always be improved, but in the current situation the question is not what is the best drug, but whether people can get a good-enough drug or not. Being somewhat sarcastic: If somebody is beyond 80 and gets ill with COVID-19, questions about possible negative effects on fertility or damage to the unborn child in pregnancy are not the main concern.

That argument of course is valid only in emergency treatment for persons that are seriously ill. The situation with vaccines is very different: They are given to healthy persons with a risk of dying from COVID-19 lower than 0.1% as of so far accumulated statistics, so there risks from side effects of the vaccination obviously are to be considered and limited with high confidence. But when I'm infected and likely to die from COVID-19 anyhow, I don't care so much about side effects of the preparate on my liver, as long as they're not likely to kill me faster than COVID-19.

That point of view seems to be missing in the discussion considering possible current runways. As soon as there is some confidence that COVID Moonshot results might save lives, there is no justification to deny these results (in form of chemicals a person could take, not paperwork) to persons ill with that disease. This most likely does not fit into standard drug production and distribution schemes. But then on one hand a lot of psychedelic drugs are produced and distributed with much less ethic justification. And on the other hand such situation should justify official, legal procedures beyond lengthy standard therapeutic certification processes. With that in mind, Project Moonshot should consider a minimum set of tests as quick as possible to make sure what has been developed so far is more likely to save the life of somebody in a high-risk group and ill with COVID-19 than take it. That should happen beside further attempts to improve the results and go through lengthy tests.

Flame shield up

F@H is not a drug company.

F@H does research and offers it freely and without attribution to all. (Mind you, drug companies are most likely to use that research, but it is free to all)

As I (mis?) read your post, I thought you were expecting F@H to produce drugs themselves. That is not going to happen, most of F@H's researchers are affiliated with an academic institution.

Universities definitely do develop vaccines, cures and new test methods. The NTNU university in Norway has developed a test method using microbeads, which is uses a lot less reactant than other tests - making it possible to test more people. Oxford University in cooperation with the drug company AstraZeneca did develop a vaccine, which is now being administered in the UK. The Oxford vaccine was approved on an accellerated schedule, precisely due to the considerations that you mention here:

ThWuensche wrote:In that situation - once there is a potentially potent treatment - not making that substance available to people can not be justified. If I have a chance of dying with 50% probability anyhow and if I could take some substance that might help me and has a probability of killing me with less than 10% probability, then I should have that substance available.

This is a classic "risk assessment" or "cost/benefit analysis" - the UK has decided that since they have so much infection right now, it is acceptable to take a higher risk for adverse effects due to the benefit. If there had been no active pandemic in the UK, the vaccine would not yet have been approved.

There does have to be some testing of efficacy and safety before it's rolled out though. We've seen serious adverse effects from drugs before, and we shouldn't take unnecessary risks. (Like Lyodura and Thalidomide.)

Basic study of the actual virus has found a location that is a very promising for disabling its camouflage, so that the immune system can destroy it: https://foldingathome.org/2020/12/16/sa ... potential/ This shows that basic research of protein folding also can find promising results. And when you learn about protein folding in muscles or in cancer cells, you might actually discover something that is applicable for a different disease than the one you started studying.

The Covid Moonshot is about as close to applied research as F@H gets, I think, because they're studying candidate compounds that target the Covid-19 virus. Some of the other Covid-19 projects are more about understanding the virus itself, but the Moonshot sprints are about studying actual compounds. Unfortunately, new compounds have to be tested for toxicity and adverse effects before they can start human trials. And even compounds which looked promising in vitro (like Chloroquine and zinc) might turn out to not be effective when they are actually tested in a clinical trial. If the Covid Moonshot finds a compound that it shown to work in an in vitro assay and is safe in animal testing, and can be synthesized in an economical way, then many drug companies can start clinical trials without paying for a patent. It would be ethical to credit the Covid Moonshot if they use the work from it, but they don't have to pay anything.

gunnarre wrote:If the Covid Moonshot finds a compound that it shown to work in an in vitro assay and is safe in animal testing, and can be synthesized in an economical way, then many drug companies can start clinical trials without paying for a patent. It would be ethical to credit the Covid Moonshot if they use the work from it, but they don't have to pay anything.

I am all in favor of Covid Moonshot, and have seven Nvidia cards on it plus to big Ryzens for the CPU work.

However, the common misconception is that patents are holding up the progress of drug delivery to the market. In fact, they facilitate it by allowing companies to make money on their research and testing, which runs into many millions (often billions) of dollars. In fact, the main hindrance to developing more antibiotics that avoid resistance to germs is the lack of profit potential. And the cost of development is not just finding the drugs in the lab, but testing them in animals and eventually humans, which is usually the biggest cost of all.

Fortunately for COVID research, various governments are helping to fund and conduct the trials. It will be necessary for Covid Moonshot to somehow plug into that, since without the potential for patented drugs, they won't find much private money for it. It is not by accident that all the most advanced vaccines (Pfizer BioNTech and Moderna, for example) are privately funded.

By the way, Dr. David Baker of Rosetta/IPD has a rather elegant solution. After doing the public research, he takes advantage of that by setting up companies to commercialize the results. Maybe Covid Moonshot needs something like that.

JimF wrote:

gunnarre wrote:If the Covid Moonshot finds a compound that it shown to work in an in vitro assay and is safe in animal testing, and can be synthesized in an economical way, then many drug companies can start clinical trials without paying for a patent. It would be ethical to credit the Covid Moonshot if they use the work from it, but they don't have to pay anything.

By the way, Dr. David Baker of Rosetta/IPD has a rather elegant solution. After doing the public research, he takes advantage of that by setting up companies to commercialize the results. Maybe Covid Moonshot needs something like that.

But IPD's angle is a bit different. They design proteins from scratch, to treat diseases. FAH's research is a bit morde fundamental (protein folding problems and cryptic pocket discovery), but with the moonshot they're also edging more towards drug design

For those interested in IPD spinoff: https://www.neoleukin.com

OK, where are we? I know they are an academic consortium, but what state are they in?
I can look at the PostEra COVIC Moonshot website, but that does not tell me much.

I think the news announcement about industry collaboration was very encouraging
https://foldingathome.org/2021/04/20/ma ... aborators/
but I still don't know how far we have to go on COVID. Have we finished our part of it yet?

@JimF: I have to apologize for what the lack of updates from our end. We've been so incredibly busy with the sprint to nominate a clinical candidate that we haven't had a chance to provide detailed updates as frequently as we'd like.

We hope to have some significant good news to announce very soon, but for now, I'd encourage you to follow the COVID Moonshot twitter account until we can post the next Folding@home update:

https://twitter.com/covid_moonshot

There's also an email newsletter you can subscribe to if this is easier:

http://eepurl.com/hhIoIn

To very quickly update where we are:
* We have very potent lead compounds that show great antiviral activity against all SARS-CoV-2 variants of concern
* The compounds appear to be very good in standard in vitro safety panels
* We're working through an issue with pharmacokinetics with rodents, which have very rapid metabolisms. This is critical for drug approvals because preclinical work to identify appropriate safe doses for humans typically use rat and dog, and if you can't use rodents, you're generally forced to use primates instead, which would significantly slow down our entry into the clinic
* We've been working incredibly hard to identify partners and funding mechansisms that will carry us through preclinical work (which can cost millions of dollars) into clinical trials (which cost many more millions) so that as soon as we nominate a clinical candidate, we can move it into human trials as rapidly as possible

The Folding@home sprints still continue! We're up to Sprint 8, but I haven't been releasing the dashboards publicly because we're still debugging some issues with the dashboard that lead to scrambling of the compounds in data display. As soon as we get these fixed, we'll get all of these dashboards online and make more regular announcements. Here's a (sadly scrambled) preview, though!

https://fah-public-data-covid19-moonsho ... index.html

The continued sprints will be vital for both aiding in the final replacement of problematic parts of the compound for improving rodent metabolism and for the further efforts to ensure second-generation compounds are active against multiple coronavirus variants.

~ John Chodera // Chodera lab

it ain't "all academics" anymore! Amazing find Moonshot of a candidate drug. Looks like it was submitted sometime in July of 2021, and who knows how many projects we all ran of it. Fingers really crossed now!
https://www.biorxiv.org/content/10.1101 ... 3.full.pdf

They certainly can look at compounds in a very fundamental way with Folding that is not possible with other techniques.

This is why we need anti-virals, and not just vaccines. Covid will be with us for a long time, and we need to hit it now.
https://www.theguardian.com/world/2022/ ... rder-study

There has been considerable progress with identifying the right compounds recently. And the NIH funding looks especially important.

But it was announced on Twitter. I hope they fill us in here more often.
https://twitter.com/covid_moonshot?ref_ ... r%5Eauthor

My interpretation is that while it didn't bear fruit this time, it does provide a potentially viable framework for responding to the next pandemic, with just more/better resources to accomplish things faster. and the NIH grant money is to stand up that infrastructure. Eventually coming up with an available, cheap, open source, patent free oral antiviral for the 3rd world is still an important goal, so I hope they don't just wind down the effort to do that.

Thanks for the interpretation. I certainly hope that the remarkable scientific infrastructure they have in place could be used for the next one.
But the "next one" could be here already with some of the Omicron variants.

Cheap would be nice, but the only ones that work thus far are the ones developed by the pharmaceutical industry, often with venture capital funding. They do that to make money. I hope the science here is not being compromised just to prevent someone from earning it.

The traditional way of financing pharmaceuticals is that some big company funds development of a bunch of candidate compounds, and when one effective drug is found, they have to recoup all their research and development investments not just in this drug, but for all the candidate drugs which didn't work after all. Unfortunately this model makes drugs expensive, and the only way that non-rich people can afford them is if a government or charity pays the company lots of money - or the patent runs out. Also it's a market, so for drugs which are patented there is an incentive to raise the price to what the market can bear - like thousands of dollars per pill. Government regulations can come in and limit the worst profiteering, but you can't force scientists to work for free either.

Unfortunately, this traditional model might not be good for rapidly finding cheap and effective drugs that can be made generically. One part of the reason is that it's a bad financial investment, and the other is that you have to keep the research secret until you've patented it. So that's when charities, universities and public-private partnerships can step in and do some non-profit research. This non-profit research can also be completely open from the start, since there's no need to keep it secret.

So the reason for this antiviral project being patent-free and open isn't because we're against people making money - it's to address an inefficiency in both time and costs that is inherent to profit-motivated drug development. Both models can work in parallell.

That is a good explanation of why drugs are expensive. They cost a lot to develop. (That isn't an "inefficiency" in the economic sense by the way, just the cost of doing business).

But you are hoping that someone else, such as charities, etc. come in to fill the gap. OK with me. Where are they?

You're contributing to a project of one of them - the Covid Moonshot consortium and DNDi. Also many research institutions are non-profits. Many private foundations, like those run by anything from rich business owners, to churches, to charities like our national cancer society, fund research. This sometimes includes clinical trials and drug development.

The UN-backed Medicines Patent Pool also made a deal with Pfizer where Pfizer lets generic drug manufacturers in Africa and many (but not all) other low income countries make their Covid-19 vaccine completely for free. There's a degree of charity in that, but of course Pfizer already recouped massive income from selling the vaccine in developed countries. Before that deal, private charities and government organizations also bought vaccines from the drug companies for developing nations, but not enough to vaccinate all of them.

The advantage of a drug which is developed completely patent free, would be that all those kinds of deals and negotiations with drug companies won't have to take place: Once a patent-free or freely licensed drug has gotten approval, any drug manufacturer can - subject to approval of the government in their own country - make generic copies of the drug for free.