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May 2021

Left-Over Neanderthal DNA Affects Our Vulnerability To COVID-19

Biden recently called Texas “Neanderthal” (pronounced “ne-ander-TALL,” not “THall”) for doing away with pandemic restrictions. Texas did so because it has seen a sharp decline in COVID-19, and it just reported its first day with no COVID-19 deaths. Maybe Biden is right, who knows? But maybe Texan’s residual Neanderthal genes could explain its drop in infections and deaths.

Neanderthals evolved in Western Eurasia about half a million years ago and died out around 40,000 years ago, but they did leave a bit behind. In the past decade, sequencing of DNA extracted from fossils and other samples from ancient hominids have shown that Neanderthals and Homo sapiens co-existed, and even consorted, producing hybrid offspring. Almost half of the Neanderthal genome still survives, scattered among almost all modern people’s DNA. The exception is those with mostly Sub-Saharan African ancestors, since Neanderthals seem never to have lived in Africa.

Such ancient genes in modern humans have been associated with things like hairiness and fat metabolism. Some of the left over Neanderthal genes also are linked with how our system affects things like risk of lupus, Crohn's disease, allergies, and diabetes. A pair of recent papers now suggests that COVID-19 belongs on that list as well. Two long stretches of DNA we inherited from Neanderthals, appear to confer either resistance or susceptibility to severe COVID-19.

Researchers at the Max Planck Institute for Evolutionary Anthropology in Leipzig, where research on Neanderthal DNA was pioneered, published in the Journal Nature last September that one Neanderthal DNA string on human chromosome 3 provides the major genetic risk factor for serious COVID-19 illness (other non-genetic risk factors include co-morbid conditions such as age, being male, obesity, diabetes, etc.). Those who carry one copy of that archaic DNA sequence have a 2-fold risk of a trip to the ICU upon infection. Those who have two copies of that sequence, one from each parent, have another doubling of risk for serious disease. The distribution of that ancient sequence around the world is uneven, possibly explaining regional differences in the incidence of severe COVID-19. In Bangladesh, 63% of Bengalis carry at least one copy, whereas it is found in only about 16% of Europeans. Not surprisingly, it is almost absent in Africa, and more surprisingly, rare in large areas of Eastern Asia. One can only speculate that it also might be rare in Texans.

How the gene affects COVID-19 severity is not known, but one gene within the sequence encodes a protein that interacts with the cell receptors used by the CoV-2 virus to enter cells. The sequence is also thought to affect cytokine production. An over-exuberant cytokine “storm” response to infection is one way that COVID-19 leads to severe disease. It is interesting that such a cytokine response is protective against cholera and that cholera has long been a problem in Bangladesh and India. That could explain why this specific Neanderthal DNA sequence has been fixed at a high frequency in the genomes of those populations—it confers a survival advantage to an endemic infectious disease. This is reminiscent of why the sickle cell genetic trait is prevalent in Sub-Saharan Africa. That genetic trait protects carriers against malaria, so it confers a survival advantage to people living in areas endemic with malaria.

The second study, published by the same lab in February in the Proceedings of the National Academy of Sciences links another Neanderthal DNA sequence found on human chromosome 12 to protection from serious disease. Carriers of this sequence are 22% less likely to develop serious disease. About 25-35% of the population in Eurasia carries at least one copy of the sequence, while about 50% in Vietnam and Eastern China do. Even before this area of chromosome 12 was discovered to come from Neanderthals, a gene in the area was known to hinder spread of RNA viruses like CoV-1 (SARS), West Nile virus, hepatitis C, and perhaps CoV-2. It instructs cells to commit suicide when they are infected by one of these viruses, hence reducing the viral load the infected cell can pump out.

All of this provides genetic clues on why some countries and populations have been hit harder by COVID-19 than others, and why others do better.

So, just how Neanderthal are Texans? Do they have more of the good gene or just less of the bad gene? Alternatively, it might just be the chili—eat a bowl of Texas red and go maskless…..

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Independent Analyses Suggest COVID-19 Can Cause Diabetes

We know that having co-morbid conditions such as asthma, heart disease, diabetes, and others are risk factors for significant COVID-19 disease and death. Now, independent reports out of the US and the UK strongly suggest that having COVID-19 can also lead to the swift onset of diabetes, even in people with mild infections. This includes children. These observations add to the list of long-term health problems for the millions of COVID-19 survivors living with chronic conditions following infection called "long-haulers."

Some 10-30% of COVID-19 survivors develop persistent and sometimes debilitating symptoms after apparent recovery from the disease. It has been known for a few months that in a subset of these long-haulers, lingering metabolic complications require high doses of insulin suggesting that they are developing diabetes. This possible link between COVID-19 and new-onset diabetes was noticed as early as last summer and was reported in Scientific American last February. Two more recent analyses of patient data strengthen the COVID-diabetes link.

  • In the US, researchers at the Veterans Affairs St Louis Health Care System’s clinical epidemiology center recently published their findings in the journal, Nature. They used data from VA national health-care databases and found that COVID-19 survivors were about 39% more likely to have a new diabetes diagnosis six months after infection compared to non-infected users of the VA health system. This means that there about 6.5 extra diabetes cases per 1000 COVID-19 patients who are not hospitalized. For hospitalized patients, the risk jumped 5-fold to 37 per 1000, and it is even higher for patients who required intensive care.
  • In the UK, a study of 50,000 hospitalized COVID patients was published about three weeks earlier than the US study. The UK study reported that the patients were 50% more likely to develop diabetes 20 weeks after discharge than matched control patients.

How does the virus do this? CoV-2 primarily is a respiratory disease, but we have known since the early days of the pandemic that it also can ravage other organs including the kidneys, brain, and others. The leading theory of how COVID-19 can cause diabetes is that the pancreas, where insulin is produced, also can be damaged by the virus, or by the immune inflammatory response that follows infection. Other possible mechanisms are also being considered.

 Bottom line: As of this month, 153 million people around the world have been infected with the virus. That means that the pandemic has caused a LOT of new cases of diabetes, a chronic disease, for the world to absorb. To monitor global COVID-related diabetes, a world-wide registry has been set up by King’s College London and Monash University in Melbourne. Almost 500 doctors around the world so far have agreed to share data via the registry.

Maybe this information will convince people who down play the disease by only focusing on the low mortality rate of COVID-19 that they also need to consider the accompanying long-term health consequences of the disease.

Why It Is Necessary To Vaccinate Kids

Vaccine makers are applying to the FDA for approval to give the COVID-19 vaccines to children. Some people have questioned the need for this since kids seldom get sick, let alone die from COVID-19. But, there is a very good reason to vaccinate them, which is to protect them, as well as the rest of us from the emerging new viral variants that are more infectious and more potent and that I discussed earlier.

Vaccines do two things; 1) they protect the vaccinated from the disease, and 2) they prevent the further spread of the pathogen and disease. A good example of the latter point is Japan and flu vaccines. A number of years ago, Japan mandated that all school kids be vaccinated against the flu. A major result was a sharp drop in flu deaths in the elderly. Kids are walking incubators for respiratory viruses and carry them home for their families to enjoy. Thus, Japan's flu vaccination program meant that fewer kids were catching the flu and carrying it home to infect their parents and grandparents. Hence, flu mortality dropped.

That is why we need to vaccinate kids against CoV-2 even though they seldom get seriously ill from it. Related to that point is the fact that the more CoV-2 spreads, the greater the chance that the virus will mutate into variants that are increasingly infectious, more deadly, and that can evade the immune response to the current vaccines. If that happened, we would be starting all over again. Hundreds of thousands, if not millions around the world would die, countless more would suffer long term consequences from COVID-19, and the disease could very well become more serious in young people. We already are seeing increases in infections and hospitalizations in younger, healthier people from the viral variants that already have arisen in the UK, South Africa, Brazil, and India.

We need to vaccinate kids in order to slow as much as possible transmission of this virus in order to minimize the development of potentially more deadly variants.

What Caused India’s Devastating Second Wave?

Understanding what contributed to a second, more intense COVID-19 surge in India can inform the rest of the world on how to avoid a similar surge for this and future pathogens. This outbreak threatens to extend the pandemic itself and drive world-wide infections to new highs, creating an enormous a breeding ground for new and potentially more dangerous viral variants. If variants emerge that are not touched by the current vaccines, the world will be at square one with the pandemic. What a depressing thought.

It appears that the second wave arose due to a combination of three things: 1) India’s relaxing quarantine measures back in January, 2) the emergence of more rapidly spreading viral variants, including one that first appeared in India, and 3) a very poor rollout of vaccines to protect India’s population from spread of the virus. These are further discussed below.

  1. Relaxed safety measures. India’s second surge came after loosening restrictions, which let public complacency set in, which, in turn, was exacerbated by government officials like Prime Minister Modi and Health Minister Harsh Vardhan declaring that the pandemic was defeated. Life returned to normal. Masks went away, as did social-distancing. Weddings and parties resumed, which usually are large events in India. A new season of state-level elections ushered in big political rallies and street parades. A massive religious festival known as the Kumbh Mela took place, bringing an estimated 5 million Hindu pilgrims to the banks of the river Ganges in April. By mid-March, cases started gradually climbing again—then suddenly accelerated, becoming a vertical line rather than an upward sloping curve. The government was slow to respond. It was not until late April that Modi finally acknowledged the urgency of the situation. Local containment measures are beginning to be enacted, including shutting down the capitol of Dehli, and a few Indian states. However, Modi remains reluctant to enact country-wide restrictions like he did during the first wave. Without a more aggressive vaccine campaign, that could be a bad decision.

The more the virus spreads throughout India, and even into its neighboring countries of Nepal, Pakistan, and Bangladesh, the greater the risk that it will generate more infectious and dangerous viral variants that will not be affected by the current vaccines. If that happens, well vaccinated countries will have to start over. That is not a pleasant prospect, and is further discussed below.

  1. More infectious viral variants. India’s more deadly second wave of the CoV-2 virus can also be attributed to more infectious and more persistent viral variants. In this second wave, India, like many other countries, has been inundated with viral variants first identified in the UK and South Africa that were recently discussed in these pages. The UK variant has a mutation in its spike protein that makes it more infectious than its parent virus. The South African variant has a different mutation in its spike protein that makes the virus more resistant to some vaccines.

India’s second surge also has introduced the world to a unique viral variant dubbed the "double mutant," which was first identified in October. It is now the dominant strain in the state of Maharashtra, home to India’s financial center, Mumbai.

“Double mutant” is actually a misnomer for this variant since it has 13 mutations throughout its genome. However, it acquired that sobriquet because it has joined the UK and South African spike protein mutations in the same virus. It is a double whammy.

While scientists are still learning about the double mutant variant, India is seeing people who were previously infected become re-infected with this new variant. Also, younger and healthier people are being hospitalized in greater numbers. These observations are concerning. Similar observations of re-infection have also been seen in Brazil with yet another viral variant that was first identified there (more about Brazil in a future post). The ability of viral variants to re-infect people can be an important driver of future pandemic waves even in countries where the population is well vaccinated, but where isolation measures have been lifted or ignored.

For the country overall, the double mutant virus made up 70.4% of the samples collected during the week ending March 25, and that is compared with 16.1% just three weeks earlier, according to Covid CG, a tracking tool from the Broad Institute of MIT and Harvard. The tool mines data from the GISAID Initiative, a global database for coronavirus genomes. These data also show that the double mutant virus has already hopped to at least 21 countries including the US. In Australia viral genome sequencing showed that the double mutant made up 40% of the samples collected over the week ending April 15, compared with 16.7% a month earlier. It accounted for 66.7% of samples from New Zealand for the week that ended April 8, up from 20% a month ago. It also has been detected in California, according to Dr. Benjamin Pinsky, director of the Clinical Virology Laboratory at Stanford University. Clearly, where the double mutant virus appears, it quickly achieves dominance.

  1. Poor vaccine distribution. As of 4/30, India had only administered 15 million vaccinations, a tiny proportion of its population of 1.4 billion people. The country is the primary producer of the AstraZeneca vaccine that has run into supply chain problems causing delays in vaccine delivery. In February, Biden signed the Defense Production Act to boost U.S. COVID-19 vaccine production but that decision cut off US exports of raw materials that India needs in order to maintain its vaccine production capabilities. Thus, vaccine makers around the world, including the Serum Institute of India (SII), the largest vaccine manufacturer in the world, face a shortage of materials to make COVID-19 vaccines. The ban has garnered much criticism as resource hoarding that threatens global vaccine production. On April 16, SII appealed directly to Biden to lift the embargo of raw material exports so that vaccine production could continue. Several days later, the White House announced it would partially lift the ban for materials the Indian company needed to manufacture the AstraZeneca vaccine, specifically.

The US also inexplicably has a large stockpile of millions of doses of the AstraZeneca vaccine, that were made here, even though it is not approved for use in the US. If we are not using it, why not release the stores to the world? The Biden administration also has faced criticism for hoarding these doses that could help India and other countries around the world that also are experiencing a new surge in infections. On Friday, April 30th, the U.S. Chamber of Commerce called on Biden release the AstraZeneca vaccines to India and other hard-hit countries.

There is some irony in all of this since India is a huge manufacturer of vaccines and pharmaceuticals for the world, and likes to bill itself as the “pharmacy of the world.” India produces 60 percent of the world’s vaccines, but cannot supply its own country, partly because of reduced production due to the supply chain problems, but also because it failed to order sufficient vaccine doses. India almost completely halted vaccine exports last month in order to divert supplies to its domestic population, which is affecting supply in the rest of the world. Rather than rely on its own manufacturers for vaccines, India approved Russia’s Sputnik vaccine, and has fast-tracked the approval process for other vaccines manufactured in foreign countries. That means that while the industrialized world was being vaccinated with vaccines produced in India, the country was still looking at approving foreign-made vaccines for use in its country.

Bottom line. The combination of relaxed safety protocols, the appearance of deadlier viral variants, and poor distribution of vaccines to its people has left the country as the world’s epicenter for the pandemic. As the virus races through its huge population, all of this provides an enormous breeding ground for new variants to arise, which is worrisome even for countries that have had successful vaccine rollouts and have begun to see reduced viral spread. Let us hope this is not a perfect storm for restarting the pandemic with vaccine-resistant variants.

And India is not the only problem. In Africa, vaccination is also off to a slow start. Just 6m doses have been administered in sub-Saharan Africa, fewer than in New Jersey. Just 1% of African adults have received a first jab, versus a global average of 13%. Prepare for Africa to become the next hot-spot and breeding ground for troublesome variants, if Brazil and South America do not beat them to the punch.

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What Is Going On In India?

The situation. India is in the throes of a second major Covid-19 surge that has hit faster and harder than the first wave did. That is often how viral pandemics behave. This catastrophic second wave came after a strict lockdown of the country in early 2020 following the first wave. In January 2021 India’s Prime Minister Modi declared that the lockdown had succeeded and that they had defeated the virus, and he re-opened the country. Until March, India was recording barely 13,000 new COVID-19 cases a day, fewer than Germany or France, and a drop in the bucket for a nation of 1.4 billion people. A few weeks after Modi’s victory declaration, however, daily cases began slowly climbing, then in late March they exploded, becoming a vertical line rather than an upward sloping curve. By mid-April India reported 315,000 new cases in one day, setting a world record. Yesterday (May 5) India set yet another record with 3700 daily deaths, according to the Johns Hopkins University tracker. The case and death rates are still climbing. Today, almost 50% of the world’s new cases come from India, according to the WHO.

India has reported 2,000-4,000 COVID-19 deaths a day for several weeks now. Since the country’s health infrastructure is poor, this likely represents a significant undercount of the mortality. As of April 30, the official total death count was around 200,000. However, the official tallies do not reflect the thousands in poor and rural areas who cannot get medical care and die at home and are not counted. For example, in just one day at one crematorium in Bhopal, workers cremated 110 COVID-19 victims, but the official total death toll for the city was just 10. Experts suspect that the total death toll in India is 1-2 million.

The second wave of the pandemic also has overwhelmed hospitals across India. Securing a hospital bed, even for the critically ill, is nearly impossible. Hospitals put up signs declaring they have no beds, and families in large cities have to search for days to find beds, often hundreds of miles away. Sick people die on the roads outside hospitals and in traffic jams created by ambulances ferrying critically ill patients in search of a bed. There are images of patients gasping for oxygen while waiting to see a doctor.

Because getting admitted to a hospital is so difficult now, patients who are admitted are much sicker than in India’s first wave. The average temperature readings of second wave patients are 2 to 3 degrees higher than they were during the first wave when temperatures averaged 100-101 degrees Fahrenheit. Blood oxygen levels of recently admitted patients run lower than they did last year meaning the patients are more critical and in greater need of oxygen. The patients are also younger this time around, between the ages of 35 and 45, and often without other pre-existing conditions.

Critical healthcare necessities are in short supply in India, from intensive care beds, medicine, oxygen, and ventilators. Delhi hospitals have tweeted messages appealing for oxygen. At one Delhi hospital, 20 critically ill patients died after the hospital’s oxygen delivery was delayed seven hours. Families are often told that they have to provide their own oxygen for hospitalized family members or take them home. In a video post, the director of a hospital said they had 60 patients in need of oxygen with only two hours of supply left.

Help for India has been offered by several countries, including the US, UK, Germany and even from India’s archrival Pakistan, which offered ventilators, oxygen supply kits, digital X-ray machines, PPE, and related items.

Bottom line. This is a snapshot of what things look like in India now, almost a year and a half after the virus first introduced itself to the world. In January, India believed that its strict lockdown measures had defeated the virus. They did not. How the more deadly second wave of the virus and disease appeared, almost overnight, will be the topic of the next blog post. It should concern all of us, because it could also happen here.

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