A collaborative piece of research published in July on eLife, done by  scientists from various centers in Connecticut, Kentucky, Ohio, Tennessee, and Wisconsin, has stirred up the conversion about Covid-19. It presented a a sort of unified hypothesis about SARS-CoV-2 that can explain many of its seemingly psychotic behaviors and point to clinical interventions that are already on the market.

The title of the paper is “A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm.” It is rather obscure for the lay person, and it certainly doesn’t sound revolutionary. But those who understand have described it as so. Why?

While it is only the tip of the iceberg in terms of Covid-19 research, this work brings together various previously disjointed pieces of knowledge and offers a rather astonishing view of the Covid-19 landscape. And, just as the tip of an iceberg, it sits on a huge amount of previous works that made possible this very visible one.

Using what they learnt from the previous research, the scientists loaded their data onto a supercomputer called Summit to run 2.5 billion correlation calculations on thousands of samples from Covid-19 patients and controls (people not infected). By the way, it took Summit abut a week to run those calculations.

Setting the Scene

I will try to summarize its content without any of the complex biochemistry that it refers to.

To do this, I will tell you the story of SARS-CoV-2 as a mole in “Trojan Horse.” By now, we have all heard that the virus has spiky proteins that it uses to attach itself to the host’s cells. The host is us, by the way, the people that the virus infects.

Its protein spikes happen to fit right into ACE2 receptors’ nooks, like a lock and key situation. ACE2 is the Trojan Horse that ushers the virus into the body. (The virus also attaches to another receptor, but we’ll stick to one here.) ACE2 or angiotensin converting enzyme 2 is a protein involved in a vital biochemical pathway that regulates processes such as blood pressure, wound healing, and inflammation. This pathway is called RAAS, for Renin-Angiotensin-Aldosterone System (also called RAS).

The Characters

The RAAS pathway is one of the characters in the unfolding of the Covid-19 story. It consists of a cascade of enzymatic processes that balance vasoconstriction and vasodilation (narrowing and opening of the blood vessels) as well as blood viscosity, thereby adjusting blood pressure.

The fact the the virus messes with blood pressure is one reason why people with hypertension and cardiac conditions are at higher risk: the virus imposes greater burden on a system already stressed.

Normally, the narrowing of blood vessels is controlled by the Vasoconstrictive ACE Axis of the RAAS system. What an ominous name, right? But this axis or arm, as some call it, basically involves two hormones, renin and angiotensin-converting-enzyme or ACE that trigger a series of protein transformations to ultimately yield Angiotensin 2 (Ang2). Ang2 binds to receptors in the cells (called AT1), and that binding prompts a sort of compactor mechanism with a constricting effect, that is, it closes up the vessels (not completely, of course) and thus elevates blood pressure.

The balance to this narrowing mechanism is the equally ominous Vasorelaxant ACE2 Counter Axis. This axis has anti-hypertensive properties, it lowers blood pressure. The bigger angiotensin 2 is broken down (by hydrolysis or water fracturing) into angiotensin 1-7 and 1-9. These smaller compounds bind with different receptors and trigger a vasodilating effect, similarly to how the release mechanism of the compactor opens it up.

Two other characters are important in this Trojan horse story: bradykinin and hyaluronic acid. Bradykinin is a small protein (a peptide hormone) that dilutes blood viscosity (by preventing the clumping of platelets in the blood) and opens up blood vessels (by relaxing smooth muscles). This is not done by bradykinin alone but by a series of compounds that bradykinin orchestrates, including prostacyclin, which you may have heard is used for pulmonary hypertension.

Bradykinin, like other kinins, increases vascular permeability and is involved in pain perception. The result of its dilution and permeability powers is a decrease in blood pressure. Another interesting effect is that it induces thirst in mammals.

Now, let’s introduce the last character, hyaluronic acid or HA. Many will know it as a skin care humectant used for its ability to draw and hold water. Indeed, in the body, it is a polymer (or large molecule) that can absorb more than 1,000 times its weight in water! HA plays a lubricating role throughout the body; its production increases during injury to promote wound healing and has a role in activating inflammatory cells to enhance immune response.

This is all under normal circumstances. Now, let’s see what happens when SARS-CoV-2 infects the body.

The Villain: SARS-CoV-2

SARS-CoV-2 enters cells in a Trojan horse fashion by hitching a ride on ACE2 receptors. Once inside the body, the virus causes the levels of ACE in the lung cells to decrease and the levels of ACE2 to increase.

Early studies interpreted the chaos in the RAAS system balance as viral slashing of ACE-2 and ramping of ACE, resulting in higher blood pressure, vasoconstriction, inflammation, and cell damage. But, the research mentioned above actually found a far more sophisticated set of events.

To start, SARS-CoV-2 can survive the extreme pH of the gastrointestinal (GI) tract. Upon spreading into the body, the virus delivers a series of devastating blows.

The First Blow: Suppressing ACE

When the virus comes face to face with cells that in principle should launch an immune response against the invader, SARS-CoV-2 does something quite clever: in another Trojan horse-like move, it repurposes the cell guards, a protein called interferon, for its own protection. It does so by stealing the shielding power from interferon. A casualty in this battle is a messenger of intelligence called NFkappaB activating factor. This messenger usually prompts production of ACE for vasoconstriction (to narrow blood vessels). The virus slashes ACE production 10-fold. The virus acts, in effect, as a blood pressure lowering medication.

The Second Blow: Ramping up ACE2

The production shutdown of ACE (technically called downregulation) tips off the RAAS balance. While the ACE Axis is suppressed, the ACE2 Counter Axis is ramped up (upregulated). Remember that SARS-CoV-2 uses ACE2 as its Trojan horse, so it makes sense (for the virus) to replicate ACE2. In fact, the increase has been estimated at almost 200-fold!

The imbalance of a suppressed ACE Axis and a rampant ACE2 Counter Axis results in more bradykinin being produced due to lack of ACE and more Ang1-9 being produced due to excess ACE2. Both of these compounds, bradykinin and Ang1-9 intensify vasodilation, inflammatory pain, and vascular permeability—or leaky blood vessel walls.

The Third Blow: Hyaluronic Invasion

Simultaneously, the virus messes with the production of hyaluronic acid or HA. The genes involved in HA synthesis are encouraged to overproduce and the genes that direct HA degradation are almost brought to a halt. The result of these two shifts is an accumulation of HA in the lungs.

As you know, the lungs are a pair of spongy, air-filled organs. The air is housed in the alveoli, which are tiny permeable balloons that bring oxygen to the bloodstream. When excess HA in the alveoli “absorbs” the fluid now dripping from leaky blood vessels, the alveoli turn not just into water balloons but Jell-O-filled balloons that are no longer permeable. In Figure 1, the research team illustrated the closing of this air exchange border. This causes the dry cough we heard so much about in covid-19 patients: they are literally gasping for air.

Figure 1: Formation of a HA-hydrogel that inhibits gas exchange in the alveoli of COVID-19 patients.

Source: https://elifesciences.org/articles/59177#s2 

The Bradykinin Storm Turns into a Category Five Hurricane

These series of small changes caused by SARS-CoV-2 conflate to create a worst case scenario, where the overdrive of mechanisms for lowering blood pressure creates leaky blood vessels and the overproduction of a lubricating substance creates a gel pool that drowns the cells and processes around it.

The research paper had another illustrative visual, shown in Figure 2.

Figure2: Systemic-level effects of critically imbalanced RAAS and BK pathways.

Source: https://elifesciences.org/articles/59177#s2

Rebuilding

While the research was focused on understanding the mechanisms of Covid-19 infection, it also points to clinical interventions to explore, particularly those already available on the market for increasing ACE, decreasing BK, or blocking BK2 receptors (which, as their name indicates help BK run amok during the infection).

Another suggestion points to the control of renin levels (the R in the RAAS pathway) through Vitamin D supplementation. Vitamin D promotes calcium absorption in the gut and maintains the balance of other minerals. Through its role in mineral balance,  Vitamin D also has a strong supporting role in the balance of the RAAS pathway. The medications suggested for these interventions are presented in table 1.

The published paper of course emphasizes the importance of testing these interventions through well-designed clinical trials. The paper closes with a great suggestion: “Given the likely future outbreaks of zoonotic viruses [originating in animals] with a similar outcome, it would be in the best interest long-term to invest in the development of small molecules that can inhibit the virus from replicating or suppressing the host immune system […]. In the meantime, our analyses suggest that prevention and treatment centered on vascular hyper-permeability and the suppression of hyaluronan [the precursor to HA] may prove beneficial in fighting the pathogenesis of COVID-19.”

Table 1: Potential therapeutic interventions, their targets, and predicted effect. 

Source: https://elifesciences.org/articles/59177#s2

In October 2019, the World Economic Forum, the Johns Hopkins Center for Health Security, and the Bill & Melinda Gates Foundation worked on a pandemic simulation (a mock-up) called Event 201.

The simulation was an exercise to understand the challenges of a pandemic and figure out ways to respond. For the scenario, the group modeled a fictional coronavirus pandemic. It was not and could not have been a prediction of Covid-19.

They hypothesized (imagined) that a new type of coronavirus appeared. There are now 7 types of coronaviruses that affect humans. Coronaviruses are common in animals (particularly, bats) and, occasionally, they “jump” to humans. They are called “zoonotic,” literally meaning a disease that humans get from animals.

The Purpose

Real epidemic events are increasing, and have health, social, and economic consequences. Therefore, it is important to understand the risks, measures, and collaboration that would be needed during a pandemic.

The Simulation

Event 201 simulates an outbreak of a fictional coronavirus first transmitted from pigs to people in farms in Brazil. Remember, this is all a mock-up, running on computers, much like a video game. The model was based on the coronavirus SARS-CoV. It is a pathogen (disease-causing agent) that causes Severe Acute Respiratory Syndrome. This is a real illness that affects your airways and causes dry cough, headache, discomfort, and body aches. Some infected people suffer from diarrhea, and most develop pneumonia.

The spread in the model is slow at first. But, eventually, the virus adjusts to its new human hosts and gets good at jumping from person to person. Person to person transmission rapidly grows in dense, low-income neighborhoods, and finds its way to big cities.

From big cities in South America, the disease travels by flight to Portugal, the United States, and China and then elsewhere. At first, some countries seem able to control it, but the diseases comes back (is reintroduced) and no country can keep it under control. The simulation uses only 300 US and 300 international cities in its model.

In the first year of the simulation, no vaccine is developed. The only thing the simulation had to help the sick was a fictional antiviral drug (a medicine to treat the sick). But, in the simulation, that drug cannot stop the spread of the disease.

Since this fictional coronavirus is a new pathogen, all humans are “susceptible”, meaning we are all prone to catching the disease (like we are for real about Covid-19). For old diseases, humans develop “herd immunity” (also called community immunity). The word “herd” refers to the fact that we humans are indeed a pack of animals in nature! Herd immunity means that enough people can resist an infectious disease because they got a vaccine or caught the illness. Enough immune people make it unlikely for the disease to spread from person to person. (This is why vaccines are SOO important! People who cannot get a vaccine, like newborns and those chronically ill, get protection from the community barrier.)

During the initial months of the simulated pandemic, the number of cases doubles every week. The simulation also keeps track of the deaths and the social and economic consequences, which become more and more severe.

The simulation ends after 18 months of pandemic spread. In its fictional outcome, the disease kills 65 million people. The spread slows down at this point because there are very few “susceptible” people left. That means people are no longer prone to catching the disease because most have caught it and recovered.

The simulation suggests that the spread of an infectious disease like the fictional coronavirus would continue until there is an effective vaccine or until 80-90 % of the global population has been exposed. From that point on, the disease becomes an “endemic” childhood disease. An endemic disease is a disease that is constantly present in an area or population, but in relatively low frequency. For example, HIV is endemic in the US, where 1 in 300 people are infected, ) and Hepatitis B (HBV) is endemic throughout the world.

The Takeways

The group concluded that a new severe pandemic would cause grave illness , suffering, and social and economic disruptions worldwide. To them, the Event 201 pandemic simulation of 2019 “vividly demonstrated” gaps in readiness and in global communication and collaboration needed to respond to such a threat. They issued recommendations for “public-private cooperation for pandemic preparedness and response.”

As the event organizers emphasize, their simulation is not a prediction of our actual situation. But some of their recommendations are proving useful in the current, and actual, pandemic of Covid-19.

One more fact I want to highlight about our real Covid-19 pandemic: the unintended good from this unexpected evil is that we might be helping curve climate change! The shelter-in-place has slowed down pollution and greenhouse gases. It has been a “vacation for the planet” (in the words of my daughter) that we should consider giving again, for everyone’s sake.

Homeschooling is not an easy feat, but it can be done, even if you are not a teacher.

Many friends and colleagues have approached me for tips about homeschooling as I have homeschooled my three children at various points in their lives and in several states. (The rules for homeschooling change by state, but with school closures, that’s the least of our concerns.)

The most important thing is keeping kids engaged and keeping them learning. “Their brains are in constant development,” says Dr. Telma Picante, an expert in language acquisition and childhood development.

If you are stickler for order, you can consult the Common Core Standards for a description of what students should know and be able to do in each subject in each grade. (The link will lead you to the California Department of Education, but the standards are pretty much the same across the country).

And a big disclosure before I begin the list: I have no ties to any of the resources and companies I list here, no payment, no gifts, zilch. I truly believe they offer good stuff.

STEP 1 – Start Small: Help your kids find something they are interested in

You Don’t Need to Address Every Subject at Once! Check your school or school district web site for guidance. Many are assembling resources for families.

If your kid has a preference for a subject or a topic, start there. It will be easier to add on to that if this shelter-in-place continues.

If you don’t know where to start, peruse some resources that have a variety of topics available. BrainPOP, usually a paid education website, has just made available some of their resources for free to schools and families impacted by school closures. They build content around different topics, make videos where a curious boy and a robot investigate it, and have activities and lesson ideas available.

Let your kids roam the websites and find something that piques their interest. Extra screen time for a limited time is not a big deal.

Another multisubject site, usually paid, but now offering some free resources is IXL. It is a task-oriented site where kids work on skills based on grade level and subject and earn badges along the way. My kids found it could get repetitive, but you don’t need to have your kids finish every single lesson.

If they are into a particular topic, whether it’s dinosaurs, rockets, or baking, you can use it as a bridge to different activities. At home, we worked on teamwork, taking turns, fractions, metric system, and the biology of taste and digestion while baking cookies and making home-made pasta.

STEP 2 – Establish a Routine: You don’t need to enforce it with a bell, but a schedule really helps

A schedule doesn’t need to start at 8:00 sharp. It is ok to let the kids sleep in a bit. In fact, many really need it! I have two night-owls and an early-bird. I was mindful of this while homeschooling. Change up what the kids do at their peek time to keep their brain engaged. This may be as simple as starting every day of the week at the same time but with a different task or topic.

Include chores and family projects that may have been part of after school activities into your new schedule. Now with my three kids at home for breakfast, lunch, and dinner, I’d go insane if they didn’t help me wash dishes!

A site I’ll share here is AdaptedMind for math and reading for K-8 kids. It offers a 1-month-free-trial, which might be just the ticket these days.

Include time for physical movement. You can just dance, use dance games, play with your pup, play tag or throw hoops in your backyard if you have one. When we were in Florida and the weather outside was just too hot and humid out, we all did follow along video of mild exercise. In some areas, you can still ride a bike outside, provided it’s safe and people keep their distance. Check with recommendation for your area.

Outdoor time is also a great way to stimulate production of vitamin D. Research suggests that many Americans lack vitamin D, and this deficiency is linked to chronic conditions. Make sure you don’t try new things suddenly. Even yoga can be strenuous if done wrong. Something that counts towards physical activity is a good spring cleaning of the garage! All that going back and forth and carrying things (make sure no one is lifting too much weight, we don’t want any sore backs)

Of course, no routine would be complete without reading on paper, the old-fashioned way. Set up time to read or re-read if that’s all you can get your hands on for now. It is also time away from the screen. If your kids read a book already, help them find a new angle. If they don’t love annotating the book, they can create flashcards or notes about a certain character, or issue in the book.

Handwriting is utterly important. Not typing, handwriting. It truly wires their brain for success. Many experts now see the loss from deprecating handwriting at schools. And lots of evidence shows they are right.

Writing, which is the next step, is trickier, but don’t despair, just encourage your kids to write. There will be time for polishing and editing. If you are interested in resources for writing Traits of Writing: The Complete Guide for Middle by Ruth Culham, and The Writing Revolution: A Guide to Advancing Thinking Through Writing in All Subjects and Grades by Judith C. Hochman  and Natalie Wexler (I believe this is available on Kindle).

A great series for writing, math, and more is the DK Series Help Your Kids With. You can get Help Your Kids With Math, Language Arts, Science, Computer Coding, Study Skills.

STEP 3 – Go on Virtual Field Trips

I used to use the afternoons for field trips with my kids. In the mornings, we’d run through our academic part of the day and do at home projects, and then we’d take off to an outing. We visited, libraries, bookstores, museums, aquariums, parks, train stations, and restaurants. I know we cannot do any of these in person right now. But many of these establishments are offering virtual tours!  Some of the ones I love are:

Musée d’Orsay, Paris, where you can see works by Van Gogh, Monet, Cézanne, and Gauguin, among others. My favorite museum for its architecture, its re-purposing project from train station to gallery is available through Google Arts. And its many impressionist works can spark art projects galore!

Musei Vaticani, Vatican City, with some of most celebrated art pieces in the world. You can tour the Sistine Chapel as if you were by yourself. And you can see pictures from the Gallery of Maps restoration. Something really cool: the historic map of Venice (below) is almost exactly the same as the one you can see today on Google maps—minus a parking structure on the “face of the fish.”

British Museum, London, where the ancient Rosetta Stone and famous Egyptian mummies are housed. I confess, I wanted to be an Egyptologist when I was a child. I am a translator and have Rosetta stone mementos all over the house: mousepad, water bottle, even a real-scale replica that I’ve used for school art exhibits.

National Gallery of Art, Washington, D.C.  offers two online tours through Google Arts, one on fashion and one on Dutch art.

National Museum of Modern and Contemporary Art, Seoul is also available for tours through Google Arts.

Van Gogh Museum, Amsterdam has the largest collection of pieces by Vincent van Gogh.

The Louvre, Paris offers some virtual tours. You cannot see The Mona Lisa, but you can see the Sphinx in their Egyptian exhibit. The Riddle of the Sphinx is a great conversation starter about thinking outside the box! (A book I love for this is Two Ways to Count to Ten.)

Uffizi Gallery, Florence has a wonderful digital archive that includes all kinds of details of the works, and virtual exhibits called HyperVisions. Their latest, On Being Present, is part of the Black History Month Florence program. This museum houses my favorite painting in the whole world: Spring, by Sandro Botticelli. Although it has many facets, I see it as a celebration of women, love, and perseverance.

Several other art museums and galleries are included on Google Arts & Culture’s collection, and more are coming online.

Many aquariums have lots of fun and educational material on their web sites and live web cams! You can visit the Monterey Bay Aquarium. Some aquariums are finding interesting things happen now that they are closed to the public. In Chicago, penguins were allowed on a field trip! This is a great conversation started about ways to balance human activity and nature.

Step 4: Use TV and Apps to Your Advantage!

There are many wonderful apps out there. Two that my kids and I have loved:

Stack the States. and Stack the Countries, fantastic games to learn about geography and history, and ones where your kids won’t outpace you in three moves, showing them that you can know a thing or two as well!

For younger kids, FunBrain has some cute games with interesting information.

And remember, your phone is loaded with apps! You can use the calculator on your phone to check on mental math quizzes. You can use the world clock to talk about time zones. Time zones are a key piece in the puzzle of National Treasure (the movie), so you can watch the movie and discuss daylight savings time.

About watching TV. So many interesting options. If you and your kids have not watched Avatar, The Last Airbender (and even its Sequel, The Legend of Korra) is the best animated series ever. So much to talk about. And yes, there is some fighting, but there is sooo much more. Philosophy, life choices, life lessons, second chances. Truly a gem. Another fun one: Phineas and Ferb, you can get into science and tinkering with these two half brothers who dream up outrageous concoctions. We once built a maze out of cardboard boxes that lasted for weeks!

For little ones, The Berenstain Bears, Dragon Tales, and, truth be told, a lot of Barbie movies, they have been really empowering! (Barbie in the Nutcracker, Barbie of Swan Lake, Barbie as Rapunzel, Barbie as the Island Princess, Mermaidia, Fairytopia, and Mariposa and the Fairy Princess.

Step 5: Do Recess: It is a Thing Even in Homeschooling

Just because you are home, it does not mean recess is over. And though recess has even been questioned at school, research supports recess!!! Recess serves as a needed break from focusing on any task (basically, why coffee rooms exist!), especially challenging ones, like learning anything that literally rewiring your brain, as school-aged kids do every day!

Recess also offers cognitive, social, emotional, and physical benefits. If you have more than one kid, let them play and find their own rules (watch over at a distance if you must to ensure their safety).

Let the kids goof around, make a funny video, get into a pillow fight, mess around with the Legos without a plan, o just sit there. Children love exploring the world through interactive experiences. These experiences help kids process and integrate information they were learning during class time.

Recess is also meant for you! If you have little ones, take “me time” when they rest. With older kids, it’s easier to set them up and “disappear” for a bit. My breaks these include reading, talking on the phone with family or friends, and even reorganizing a drawer. Just be kind to yourself.