A Supercomputer Analyzed Covid-19, and an Interesting New Theory Has Emerged

Source: Elemental

A closer look at the Bradykinin hypothesis


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Earlier this summer, the Summit supercomputer at Oak Ridge National Lab in Tennessee set about crunching data on more than 40,000 genes from 17,000 genetic samples in an effort to better understand Covid-19. Summit is the second-fastest computer in the world, but the process — which involved analyzing 2.5 billion genetic combinations — still took more than a week.

When Summit was done, researchers analyzed the results. It was, in the words of Dr. Daniel Jacobson, lead researcher and chief scientist for computational systems biology at Oak Ridge, a “eureka moment.” The computer had revealed a new theory about how Covid-19 impacts the body: the bradykinin hypothesis. The hypothesis provides a model that explains many aspects of Covid-19, including some of its most bizarre symptoms. It also suggests 10-plus potential treatments, many of which are already FDA approved. Jacobson’s group published their results in a paper in the journal eLife in early July.

According to the team’s findings, a Covid-19 infection generally begins when the virus enters the body through ACE2 receptors in the nose, (The receptors, which the virus is known to target, are abundant there.) The virus then proceeds through the body, entering cells in other places where ACE2 is also present: the intestines, kidneys, and heart. This likely accounts for at least some of the disease’s cardiac and GI symptoms.

But once Covid-19 has established itself in the body, things start to get really interesting. According to Jacobson’s group, the data Summit analyzed shows that Covid-19 isn’t content to simply infect cells that already express lots of ACE2 receptors. Instead, it actively hijacks the body’s own systems, tricking it into upregulating ACE2 receptors in places where they’re usually expressed at low or medium levels, including the lungs.

In this sense, Covid-19 is like a burglar who slips in your unlocked second-floor window and starts to ransack your house. Once inside, though, they don’t just take your stuff — they also throw open all your doors and windows so their accomplices can rush in and help pillage more efficiently.

The renin–angiotensin system (RAS) controls many aspects of the circulatory system, including the body’s levels of a chemical called bradykinin, which normally helps to regulate blood pressure. According to the team’s analysis, when the virus tweaks the RAS, it causes the body’s mechanisms for regulating bradykinin to go haywire. Bradykinin receptors are resensitized, and the body also stops effectively breaking down bradykinin. (ACE normally degrades bradykinin, but when the virus downregulates it, it can’t do this as effectively.)

The end result, the researchers say, is to release a bradykinin storm — a massive, runaway buildup of bradykinin in the body. According to the bradykinin hypothesis, it’s this storm that is ultimately responsible for many of Covid-19’s deadly effects. Jacobson’s team says in their paper that “the pathology of Covid-19 is likely the result of Bradykinin Storms rather than cytokine storms,” which had been previously identified in Covid-19 patients, but that “the two may be intricately linked.” Other papers had previously identified bradykinin storms as a possible cause of Covid-19’s pathologies.

As bradykinin builds up in the body, it dramatically increases vascular permeability. In short, it makes your blood vessels leaky. This aligns with recent clinical data, which increasingly views Covid-19 primarily as a vascular disease, rather than a respiratory one. But Covid-19 still has a massive effect on the lungs. As blood vessels start to leak due to a bradykinin storm, the researchers say, the lungs can fill with fluid. Immune cells also leak out into the lungs, Jacobson’s team found, causing inflammation.

And Covid-19 has another especially insidious trick. Through another pathway, the team’s data shows, it increases production of hyaluronic acid (HLA) in the lungs. HLA is often used in soaps and lotions for its ability to absorb more than 1,000 times its weight in fluid. When it combines with fluid leaking into the lungs, the results are disastrous: It forms a hydrogel, which can fill the lungs in some patients. According to Jacobson, once this happens, “it’s like trying to breathe through Jell-O.”

This may explain why ventilators have proven less effective in treating advanced Covid-19 than doctors originally expected, based on experiences with other viruses. “It reaches a point where regardless of how much oxygen you pump in, it doesn’t matter, because the alveoli in the lungs are filled with this hydrogel,” Jacobson says. “The lungs become like a water balloon.” Patients can suffocate even while receiving full breathing support.

The bradykinin hypothesis also extends to many of Covid-19’s effects on the heart. About one in five hospitalized Covid-19 patients have damage to their hearts, even if they never had cardiac issues before. Some of this is likely due to the virus infecting the heart directly through its ACE2 receptors. But the RAS also controls aspects of cardiac contractions and blood pressure. According to the researchers, bradykinin storms could create arrhythmias and low blood pressure, which are often seen in Covid-19 patients.

The bradykinin hypothesis also accounts for Covid-19’s neurological effects, which are some of the most surprising and concerning elements of the disease. These symptoms (which include dizziness, seizures, delirium, and stroke) are present in as many as half of hospitalized Covid-19 patients. According to Jacobson and his team, MRI studies in France revealed that many Covid-19 patients have evidence of leaky blood vessels in their brains.

Bradykinin — especially at high doses — can also lead to a breakdown of the blood-brain barrier. Under normal circumstances, this barrier acts as a filter between your brain and the rest of your circulatory system. It lets in the nutrients and small molecules that the brain needs to function, while keeping out toxins and pathogens and keeping the brain’s internal environment tightly regulated.

If bradykinin storms cause the blood-brain barrier to break down, this could allow harmful cells and compounds into the brain, leading to inflammation, potential brain damage, and many of the neurological symptoms Covid-19 patients experience. Jacobson told me, “It is a reasonable hypothesis that many of the neurological symptoms in Covid-19 could be due to an excess of bradykinin. It has been reported that bradykinin would indeed be likely to increase the permeability of the blood-brain barrier. In addition, similar neurological symptoms have been observed in other diseases that result from an excess of bradykinin.”

Increased bradykinin levels could also account for other common Covid-19 symptoms. ACE inhibitors — a class of drugs used to treat high blood pressure — have a similar effect on the RAS system as Covid-19, increasing bradykinin levels. In fact, Jacobson and his team note in their paper that “the virus… acts pharmacologically as an ACE inhibitor” — almost directly mirroring the actions of these drugs.

By acting like a natural ACE inhibitor, Covid-19 may be causing the same effects that hypertensive patients sometimes get when they take blood pressure–lowering drugs. ACE inhibitors are known to cause a dry cough and fatigue, two textbook symptoms of Covid-19. And they can potentially increase blood potassium levels, which has also been observed in Covid-19 patients. The similarities between ACE inhibitor side effects and Covid-19 symptoms strengthen the bradykinin hypothesis, the researchers say.

ACE inhibitors are also known to cause a loss of taste and smell. Jacobson stresses, though, that this symptom is more likely due to the virus “affecting the cells surrounding olfactory nerve cells” than the direct effects of bradykinin.

Though still an emerging theory, the bradykinin hypothesis explains several other of Covid-19’s seemingly bizarre symptoms. Jacobson and his team speculate that leaky vasculature caused by bradykinin storms could be responsible for “Covid toes,” a condition involving swollen, bruised toes that some Covid-19 patients experience. Bradykinin can also mess with the thyroid gland, which could produce the thyroid symptoms recently observed in some patients.

The bradykinin hypothesis could also explain some of the broader demographic patterns of the disease’s spread. The researchers note that some aspects of the RAS system are sex-linked, with proteins for several receptors (such as one called TMSB4X) located on the X chromosome. This means that “women… would have twice the levels of this protein than men,” a result borne out by the researchers’ data. In their paper, Jacobson’s team concludes that this “could explain the lower incidence of Covid-19 induced mortality in women.” A genetic quirk of the RAS could be giving women extra protection against the disease.

The bradykinin hypothesis provides a model that “contributes to a better understanding of Covid-19” and “adds novelty to the existing literature,” according to scientists Frank van de Veerdonk, Jos WM van der Meer, and Roger Little, who peer-reviewed the team’s paper. It predicts nearly all the disease’s symptoms, even ones (like bruises on the toes) that at first appear random, and further suggests new treatments for the disease.

As Jacobson and team point out, several drugs target aspects of the RAS and are already FDA approved to treat other conditions. They could arguably be applied to treating Covid-19 as well. Several, like danazol, stanozolol, and ecallantide, reduce bradykinin production and could potentially stop a deadly bradykinin storm. Others, like icatibant, reduce bradykinin signaling and could blunt its effects once it’s already in the body.

Interestingly, Jacobson’s team also suggests vitamin D as a potentially useful Covid-19 drug. The vitamin is involved in the RAS system and could prove helpful by reducing levels of another compound, known as REN. Again, this could stop potentially deadly bradykinin storms from forming. The researchers note that vitamin D has already been shown to help those with Covid-19. The vitamin is readily available over the counter, and around 20% of the population is deficient. If indeed the vitamin proves effective at reducing the severity of bradykinin storms, it could be an easy, relatively safe way to reduce the severity of the virus.

Other compounds could treat symptoms associated with bradykinin storms. Hymecromone, for example, could reduce hyaluronic acid levels, potentially stopping deadly hydrogels from forming in the lungs. And timbetasin could mimic the mechanism that the researchers believe protects women from more severe Covid-19 infections. All of these potential treatments are speculative, of course, and would need to be studied in a rigorous, controlled environment before their effectiveness could be determined and they could be used more broadly.

Covid-19 stands out for both the scale of its global impact and the apparent randomness of its many symptoms. Physicians have struggled to understand the disease and come up with a unified theory for how it works. Though as of yet unproven, the bradykinin hypothesis provides such a theory. And like all good hypotheses, it also provides specific, testable predictions — in this case, actual drugs that could provide relief to real patients.

The researchers are quick to point out that “the testing of any of these pharmaceutical interventions should be done in well-designed clinical trials.” As to the next step in the process, Jacobson is clear: “We have to get this message out.” His team’s finding won’t cure Covid-19. But if the treatments it points to pan out in the clinic, interventions guided by the bradykinin hypothesis could greatly reduce patients’ suffering — and potentially save lives.

Source: Elemental

My problem here is what criteria did they use to verify it is the virus?
Seems like everything but the kitchen sink thrown in.
Ferguson's modelling with horrendous forecasts which have fortunately not materialised would lea me to doubt the results s in the study

Chris

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Posted by greybeard

My problem here is what criteria did they use to verify it is the virus?

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It is all based upon empirically collected data. In other words, it is all information based upon the lab results and symptoms experienced by people who tested positive for coronavirus antibodies.

If I have the virus and drop a hammer on my toe that sore toe will go down as a symptom ?
Smiling.
Anything that I am suffering at the time I test positive to a failed test will go down.
The test would seem to turn positive for various reasons not specific to any particular virus - flu - cold.
Chris

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Posted by greybeard

If I have the virus and drop a hammer on my toe that sore toe will go down as a symptom ?
Smiling.

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No, of course not. Now you're being silly.

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Posted by greybeard

Anything that I am suffering at the time I test positive to a failed test will go down.
The test would seem to turn positive for various reasons not specific to any particular virus - flu - cold.
Chris

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That's not true. If you know your own body and you also know that you were healthy before, then you can also tell which symptoms come from the virus and which ones don't. I have had Covid-19, so I know exactly what the symptoms were for me, and most other people whom I know were also infected had roughly the same symptoms.

I say "roughly" because some reported a loss of smell and taste, whereas I did not exhibit that. Some had higher fevers than I did. I also had a diarrhea, but not everyone else with the virus did. But we did all experience the swollen feeling of the throat, pain in the lungs, dizziness, headaches, brain fog, a certain degree of fever, red eyes, fatigue and muscle or joint pains. And it was all very clear that these symptoms were not brought about by anything else.

Yes I was being silly, tongue in cheek.
However, it is even more "silly" to shut the whole world down and I do have sympathy for what you and others went through Frank.
I tend to look at the whole context -- a minority went through what you experienced, millions will suffer from loss of income, depression and all that follows this forced lockdown --which continues.
Your immune system is now stronger.
Out of interest did you have the flu jab before this happened ie 2019?
Chris

But can they prove this was not a designer virus before it mutated anyway ? Rhetorical question though 🌟

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Posted by greybeard

Yes I was being silly, tongue in cheek.
However, it is even more "silly" to shut the whole world down and I do have sympathy for what you and others went through Frank.

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Well, it was nasty ─ and in a way it still is, because the virus is known to cause permanent damage, and I was already battling with autoimmune problems, which the virus has now only made worse ─ but I still don't consider the degree to which I was affected all that important, given that many people lost their lives.

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Posted by greybeard

I tend to look at the whole context -- a minority went through what you experienced, millions will suffer from loss of income, depression and all that follows this forced lockdown --which continues.

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With all due respect, Chris ─ and I mean that ─ the loss of income is only the result of the fact that we're living in a capitalist economy. If the world had been governed by a form of the so-dreaded socialist economy model, then nobody would have lost any income at all, because socialism guarantees an income for everyone. Think about that for a moment, please.

As for the forced lockdowns, things are not quite as black & white as people make them out to be. The lockdowns ─ where they were respected ─ did effectively slow down the spreading of the virus, so that the health sector didn't get overloaded.

But at the same time, I do have to conclude that governments are basically winging it as they go, being torn back and forth between the opinions and advice from qualified scientists on the one hand, and lobbying industry and commerce groups on the other hand. And some of the measures ─ at least in some places ─ are really stupid.

Telling people to wear a mask if they're traveling all alone in their car or when they're jogging is stupid, and unhealthy. But at the same time, telling everyone to respect a 1.5-meter social distance ─ which is ineffective, because the virus can travel up to 8.5 meters if you're not wearing a mask ─ and then allowing party-goers to reduce their social distance to 1 meter, that's just ludicrous. So you have to maintain a 1.5-meter distance from one another, but at a party, the virus will let you get off the hook for the first 50 cm of proximity?

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Posted by greybeard

Your immune system is now stronger.

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I'm not so sure of that, and on top of that, we've already got at least one case here of a person who now contracted the virus a second time.

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Posted by greybeard

Out of interest did you have the flu jab before this happened ie 2019?
Chris

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Nope, I've never had any flu jabs.

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Posted by Agape

But can they prove this was not a designer virus before it mutated anyway ? Rhetorical question though 🌟

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No, of course not. This supercomputer analysis was entirely geared toward mapping out what exactly the virus does in the human body ─ its modus operandi and attack vectors ─ and how to best protect people against it. It doesn't say anything about the genetic origins of the virus.

Thank you for your response Frank.
The situation UK with lockdown may be different from where you are.
Basically they keep changing the rules.
They give back freedom of movement --people go abroad then are told with very little warning you will have to self-isolate for a fortnight when you get back.
Business told they can reopen with social distancing masks etc then with very little warning are told --there has been several people in your area found to have the virus and a million people in that area have to endure close down of small businesses again

An Oxford University Professor now says social distancing --masks -- lockdown does not work.
That was in a video sometime back
Who are we to believe?
Chris
The links here of recent info from same Professor
https://projectavalon.net/forum4/show...=1#post1375626

https://uk.news.yahoo.com/coronaviru...135414823.html

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Posted by Frank V

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Posted by greybeard

My problem here is what criteria did they use to verify it is the virus?

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It is all based upon empirically collected data. In other words, it is all information based upon the lab results and symptoms experienced by people who tested positive for coronavirus antibodies.

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so, terrible science & basically a bunch of informed "hunches"... sounds about right.

Like the guy who died in a motorcycle accident and was counted as a covid death, is his data in the mix as well?

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Posted by greybeard

If I have the virus and drop a hammer on my toe that sore toe will go down as a symptom ?
Smiling.
Anything that I am suffering at the time I test positive to a failed test will go down.
The test would seem to turn positive for various reasons not specific to any particular virus - flu - cold.
Chris

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Yep, seems like more propaganda to me.

Why is the DOE getting into this? (smells even MORE like propaganda to me)

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Posted by Frank V

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Posted by greybeard

If I have the virus and drop a hammer on my toe that sore toe will go down as a symptom ?
Smiling.

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No, of course not. Now you're being silly.

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Not according to the reporting methods I've observed.... it's very accurate, how many comorbidity deaths were contributed purely to COVID-19?

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Posted by Frank V

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Posted by greybeard

Anything that I am suffering at the time I test positive to a failed test will go down.
The test would seem to turn positive for various reasons not specific to any particular virus - flu - cold.
Chris

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That's not true. If you know your own body and you also know that you were healthy before,

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Do you feel like this is a common thing, or extremely uncommon? (especially in those who would seek medical attention for a mild flu)


I don't see this situation as anything but vastly overblown and a propaganda tool and the numbers keep getting revised down (only 6% of reported deaths are solely from COVID-19?? that's SHOCKING).


i "think" I had it, but it was mild and the worst was only 3-4 days... I didn't go to the "doctors" because I can manage myself fine & am not in one of the risk categories.... I don't think I am the type of people that we hear from however, it's more the go-to-a-doc-for-any-minor-thing people.

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Posted by TargeT

Do you feel like this is a common thing, or extremely uncommon? (especially in those who would seek medical attention for a mild flu)

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I would say that it was definitely extremely uncommon, both within myself and in those who had to go to hospital because of it. I have never experienced anything like this before, and I almost died of pneumonia back in 1986, so I've been around the block.

It is most definitely not a flu ─ or for that matter, a common cold ─ and I do have a background in (among other things) the medical field. As the article says, this is not a respiratory disease but primarily a vascular one ─ the respiratory effects are only a secondary symptom.

Frank I dont have the slightest challenge with what you have posted in good faith.
My concern as always is There does not seem to be a test that for sure identifies Covid as separate from previous covids or even the Flu.
The flu can cause all kinds of unpleasant things including all you have mentioned.
For sure something is causing what you experienced and many others too, but where is the valid test that says "This is Covid"
Im not dismissing that it may have been Covid you experienced just that Science has not yet for sure come up with a test that isolated the virus from all previous viruses.
So the computer modelling may have been done on a false premise that everything entered was covid without a shadow of doubt.
Obviously I dont know --but who does for sure.
Chris

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Posted by greybeard

Frank I dont have the slightest challenge with what you have posted in good faith.
My concern as always is There does not seem to be a test that for sure identifies Covid as separate from previous covids or even the Flu.
The flu can cause all kinds of unpleasant things including all you have mentioned.
For sure something is causing what you experienced and many others too, but where is the valid test that says "This is Covid"
Im not dismissing that it may have been Covid you experienced just that Science has not yet for sure come up with a test that isolated the virus from all previous viruses.
So the computer modelling may have been done on a false premise that everything entered was covid without a shadow of doubt.
Obviously I dont know --but who does for sure.
Chris

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Chris, I am not going to argue with you (or anyone else) about this ─ and if the knee-jerk science denial takes over this thread, then I'm going to leave this thread for what it is; I'm not kidding ─ but you are very, very wrong. I repeat that I come from, among other things, a training in the medical field, and I have also been educated in other areas of science, of which my favorite is the field of physics.

Covid-19 is caused by the SARS-CoV-2 virus, which is a coronavirus. Neither the flu nor the common cold ─ which is often mistakenly referred to as the flu, even though it is by far not as dangerous as the real flu ─ are coronaviruses. Just because the coronavirus tests in the USA have been botched ─ and perhaps also in the UK, which has a prime minister whose political persuasions happen to align very much with those of the head-of-state in the USA, and who exhibited the same degree of incompetence until he himself caught the virus and had to be admitted to an intensive care ward ─ doesn't mean that the scientific community in the rest of the world partakes in that sort of incompetence.

Again, with all due respect, but the denialist reactions I am seeing here at Project Avalon are based upon nothing but paranoid knee-jerk rejections of anything that even remotely reeks of the word "mainstream" ─ unless it comes from Fox News, apparently ─ as well as so-called "expert opinions" from YouTube talking heads with an agenda who can very easily influence those who never studied any sciences, and a huge amount of cognitive bias, supported by anecdotal evidence because a few mistakes have been made here and there in testing and/or counting infected people. And once again, had the US government ─ and to a lesser extent the British government ─ not been so incompetent, then those anecdotal mistakes would perhaps never even have been made.

I'm a scientist, Chris. I don't do knee-jerks and I don't listen to opinionated talking heads. I know what I know because I've studied it, and I understand it.

I think it's best to leave that one out of discussions. It's not productive at this point.

Is it fair to say that this epidemic is suspect, at least in its over-inflation by the media, and the over-reaction of authority to what seemed to be a scripted contingency plan? Is it not strange how national health boards gave way to the WHO and took their marching orders as if from a potentate? Surely we can all agree that there is a political angle to the pandemic, and that it was very timely?

Also, since there has been varying degrees of tyranny imposed on the peoples of the world because of it, there seems to be no consensus on how to best respond to it.

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Posted by Ernie Nemeth

Is it fair to say that this epidemic is suspect, at least in its over-inflation by the media, and the over-reaction of authority to what seemed to be a scripted contingency plan? Is it not strange how national health boards gave way to the WHO and took their marching orders as if from a potentate? Surely we can all agree that there is a political angle to the pandemic, and that it was very timely?

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In my opinion, no, it's not suspect at all. I see lots of human error and panic, especially among the governments, because we humans were so arrogant and complacent in assuming that nothing the circumference of the Spanish flu would ever come along again. We considered ourselves invincible. And we were messing up the planet just as badly as we were messing up each other. So Mother Nature ─ just a metaphor, because I don't do gods and goddesses, although I do see the whole of the universe as a single, sentient organism ─ decided to strike back. No Draco reptilians, no Annunaki, no Illuminati, no communists, no Jews, no baby-eating satanic pedophiles and no Deep State™. Just good old nature rising up to the challenge of having to deal with a ruthlessly predatory and destructive species like us.

And the politicians, who apart from their very royal salaries, expensive automobiles and celebrity status are no different from us ─ and certainly not versed in any fields of science ─ were panicking. They still are. It's beyond their competence levels as leaders because they're only in it for themselves. Politics pays well, you get to travel a lot, and you get your face on TV. But leadership is something they don't really possess ─ and that goes for the orange dude just as well as for those lining up to take his place. Real leaders don't run for any office. They are dropped in without a parachute and they don't even want to be in a position where they are expected to lead.

And then of course, the media are panicking too, but part of their panic is fake. Or at the very least exaggerated. Because they are commercial entities who make their living from selling printed copies, online subscriptions and ─ above all ─ advertisements from their corporate partners, and sensationalism, shock and awe are the number-one trump card ─ pun only semi-intended ─ to commercial success. They sell hyperbole, and especially so the corporate media ─ state-sponsored media tend to be a little bit better, even though they too can be sensationalist.

In the end, it's like the man said ─ may he rest in peace...:

Everyone wants to sell what's already been sold
Everyone wants to tell what's already been told
What's the use of money if you ain't gonna break the mold
Even at the center of fire, there is cold
All that glitters ain't gold

(Prince, "Gold")

But I thought the virus hasn’t actually been isolated so how can you test for that? It’s been proven the COVID test can’t even test for the virus. I can’t take the report at face value. Would need to know the criteria involved.

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Posted by selinam

But I thought the virus hasn’t actually been isolated so how can you test for that? It’s been proven the COVID test can’t even test for the virus. I can’t take the report at face value. Would need to know the criteria involved.

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https://media.giphy.com/media/zac5EvG19YCVa/giphy.gif

I wonder how many of those symptoms are also caused by (or made worse by) 5G.

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Posted by selinam

It’s been proven the COVID test can’t even test for the virus.

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That was only true in North America, and specifically so in the USA, because the US CDC had mixed up the test kits with test kits for the flu.

In the rest of the world however, the tests were reliable.

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Posted by onawah

I wonder how many of those symptoms are also caused by (or made worse by) 5G.

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None whatsoever.

Any research to back that claim?
Because I think there has been research indicting that 5G does make such symptoms worse, if not actually cause them, particularly when the brain is involved.
Exomatrix would probably know where to access the latter.

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Posted by Frank V

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Posted by selinam

It’s been proven the COVID test can’t even test for the virus.

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That was only true in North America, and specifically so in the USA, because the US CDC had mixed up the test kits with test kits for the flu.

In the rest of the world however, the tests were reliable.

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Posted by onawah

I wonder how many of those symptoms are also caused by (or made worse by) 5G.

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None whatsoever.

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