“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” (elemental).
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