Coronavirus

US Life Expectancy Finally Bounces Back Up

Game over, man! Game over!” --Bill Paxton as Private Hudson in Aliens

As I wrote in these pages a couple of years ago, the US suddenly lost a whopping 1.3 years of average life expectancy due to COVID. It had that big of an impact on the country in excess deaths. And before some moron starts saying it was due to vaccine deaths, the down turn in life expectancy, or the increase in excess deaths (i.e., deaths more than expected based on actuarial predictions) began before the vaccines rolled out and just after the virus appeared. Furthermore, the upturn in life expectancy occurred after the vaccines were delivered, as well as after the virus evolved from Delta to a less lethal variant. In the early days of COVID vaccination before vaccines were widely distributed, data showed that unvaccinated people were 11 times more likely to die from the virus than vaccinated people. At one point, 95% of hospitalizations and 99% of deaths were in unvaccinated people. The vaccines clearly prevent death, they do not cause death (unless you listen to Robert F. Kennedy, Jr. or Marjorie Taylor Greene, more on her later).

The graph below shows the dramatic drop in life expectancy beginning in 2019 and reversing about 2021. If vaccines were killing rather than saving people, you would think the curve would continue downward.

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BioX Wins The Nobel!

“If you start to take Vienna, take Vienna”— Napoleon (reportedly)

What’s the fuss? BioX won the Nobel Prize….er rather it was the mRNA vaccine that won. Correction—it was the scientists, Katalin Karikó and Drew Weissman of the University of Pennsylvania, who developed the RNA technology that went into the novel vaccine who won the prize. But their work directly led to the vaccine, a first fruit of BioX.

Readers of these blog pages might remember that about this time in 2020, that year’s Nobel award for Medicine or Physiology went to three scientists for their decades-long search to discover what caused hepatitis type non-A, non-B. It turned out to be a whole new virus, the hepatitis C virus (or HCV) that took four decades to identify. Even though it still remains a huge health problem, there still is no vaccine for it. I compared that four decade slog just to find the pathogen to how fast the novel viral cause of COVID-19 was found and a vaccine developed—all done in less than a year! I anointed the new biology that did that amazing feat, ‘BioX.’ That was rather prescient of me, since three years later, the co-founders of the COVID vaccine using BioX too were awarded the Nobel Prize.

I dubbed the new amazing post-molecular biology science that enabled such a quick identification of the novel coronavirus and development of a vaccine against it, ‘BioX’ after SpaceX. SpaceX, of course, is the name for the new way space travel is now being done. Shortly before the Nobel award for the discovery of HCV, Elon Musk’s SpaceX took astronauts in an unpiloted vehicle to the International Space Station. Then the launch vehicle, rather than being discarded as usual, was landed, upright, in the center of a bullseye on a barge off the coast of Ireland, to be reused on a future space flight--maybe to Mars? The whole thing was developed in a fraction of the time at a fraction of the cost of what NASA had historically been doing. NASA’s technology was rendered archaic by SpaceX, which introduced us to a new era of space travel.

The breathtaking speed with which a new biology discovered the SARS-CoV-2 virus and then developed a safe and effective vaccine against it ushered in a new post-molecular biology world I dubbed ‘BioX’.

Now the details. But as breathtaking as SpaceX is, it was not developed overnight in a vacuum. It arose on the back of decades of NASA engineering R&D, which included some spectacular failures and even a few tragic deaths. Similarly, as breathtaking as BioX was with the rapid identification of a novel virus and development of the new mRNA vaccines to a wholly new disease, that technology too was built on the back of decades of hard work, punctuated with many failures, but also flavored with impressive perseverance on the part of a few individuals.

There are two major components to the novel COVID vaccines—the mRNA which generates the viral protein to which the immune response is made, and the lipid nanoparticles that encapsulate and protects the fragile mRNA from a world that is hostile to mRNA. Both components took very separate, decades long, twisting, uphill roads to develop. Both nearly met with failure. And both came together with spectacular success. BioX!

  • The mRNA. Weissman, and especially Karikó, languished for years on the fringes of science with a, then, very weird idea of using mRNA to produce drugs or vaccines. Their collaboration began with a chance encounter at a UPenn copy machine in the 90s and went downhill from there as recently told in the Wall Street Jounal. Funding for their work was hard to come by. Karikó was banished to an office on the outskirts of the campus and languished in a non-faculty position for years. At one point, she had to take a demotion to simply keep a job at Penn.

They just could not get their idea to work. The mRNA was too fragile and too short-lived to work with and produce the desired proteins when they tried to express it in cells or animals. The fact is that there are ubiquitous enzymes all around us called RNases that have a ravenous appetite for mRNA. RNA molecules, especially mRNA disappear almost as fast as one can purify or make them, let alone then try to get them into cells in tissue culture or into bodies. On top of that, when naked mRNA is injected into a body, it elicits a powerful immune response that further quickly degrades it. Note that there are several different types of RNA, and mRNA is the most fragile and hardest to work with, but it is the type that provides the message that turns a genetic code into a protein molecule like a spike protein, which is why it is used in the vaccine.

The researchers had great difficulty getting grant funding for their research because no one believed it would go anywhere. When they could produce some data, they had a very hard time finding journals to publish it. No one was interested because no one believe that there was any utility in the whole premise of using mRNA as a therapeutic tool. In the publish-or-perish world of academia, such negative peer pressure usually is the kiss of death. They should have seen the writing on the wall and been teaching high school biology. But for some reason, Karikó continued to have faith in her idea even though no one else did. For some reason, she persevered.

After dogged determination and ignoring all the naysayers, she eventually had a major breakthrough after a doing a simple experiment. They found a simple way to protect the mRNA from the immune response and published this in 2005. It opened the field and colleagues minds about using mRNA as a possible therapeutic tool. But there still was the problem that mRNA was exquisitely sensitive to RNase enzymes that were everywhere—on your fingers, in your breath and blood, even on sterilized surfaces—the enzymes are incredibly stable molecules and very hard to destroy. Life intended mRNA to be short lived molecules, not to be used in vaccines.

It wasn’t until folks paired the immune-stable mRNA of Karikó and Weissman with a way to protect the molecules from RNase enzymes that mRNA vaccines became possible so they could win the Nobel Prize. Lipid nanoparticles did the trick.

  • The lipid nanoparticles. The story behind the development of the lipid nanoparticles used to deliver the CoV-2 viral spike mRNA sequence to cells so they could use their normal gene expression machinery to put the spike protein on their surface and generate an immune response is a long one. In that regard it is quite similar to the long, arduous story behind the development of the therapeutic mRNA. Early on, neither technology was believed possible or useful by the scientists’ peers. Both groups had very hard times getting their scientific feet on the ground. Both nearly failed. I described Karikó’s struggle above and in March 2021 I wrote in these pages about the professional plight of Bob Langer who, in the 70s, had a vision for using liposomes (short for lipid nanoparticles) for delivering fragile bio-molecules and drugs to cells (you can read that post here). Briefly, his idea was to create mini-cells in which to package and protect fragile therapeutic molecules and then deliver them to cells and tissues in the body. The liposomes containing the fragile therapeutic molecules would fuse with the lipid membranes of cells and disgorge their contents into the cells. Many people told him it was not possible and he had his first nine grant applications rejected—and this was a time when medical science research grants were easy to get (when I was in graduate school in the early 80s, NIH grant applications had a 50% success rate. By the time I became a faculty member in the late 80s that dropped to 10%). Langer, like Karikó, also could not get a faculty position because people did not believe in his research. Also like Karikó, for some reason Langer persevered.

Also like Karikó, Langer too succeeded—eventually. It took a long time. The technology he successfully developed was first used to package a drug used to treat a rare genetic disease that causes nerve and heart damage. It also was used to package mRNA for an Ebola vaccine. From an ignominious beginning, Bob Langer became a professor at MIT where there now is a bioengineering lab named after him. That is not quite as nice as winning a Nobel prize, but high recognition still.

Along the way, he also co-founded a small biotech company named Moderna that was focused on developing mRNA vaccines for infectious diseases, cancer and other diseases. Then COVID came calling and Moderna immediately pivoted, and along with BioNTech, NIH, and Pfizer, quickly gave us mRNA vaccines delivered in liposomes that saved millions of lives from COVID.

That is how BioX technology led to the Nobel prize this year.

The bottom line. BioX, like SpaceX, was built on decades of hard research that was punctuated by painful failures, but highlighted by dogged determination. Both technologies, BioX and SpaceX, are here to stay at least until the next amazing thing replaces them. You can bet that that next amazing thing will have been developed on the back of determined researchers who very possibly will be working at the fringe of their professions and may flirt with professional failure early on. You can also bet that the next amazing things will be built on the backbone of SpaceX and BioX. That is how science and engineering painfully progresses.

So, when you hear someone say that the mRNA vaccines are experimental like I very often do, tell them the truth. They were built on decades of hard research going back to the 70s.

Stay tuned for a coming post on the future of BioX, which is here to stay for a while. New mRNA vaccines are being developed for previously vaccine-impossible diseases including HIV, cancer, and various animal diseases. Work also is underway for a universal flu vaccine.

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Politics: A Risk Factor For Death From COVID?

What are you gonna believe, medical science or dubious talking heads?

In 2021 former Green Bay Packers quarterback, Aaron Rodgers, said he was “immunized” against COVID. He wasn’t. He claimed to have done “research” and learned how to get an infusion of antibodies and take some unproven ‘medicine.’ His ‘research’ was talking to radio pundit and hot-air purveyor, Joe Rogan. How many more people like Rodgers listen to the wisdom of the likes of Rogan or Tucker Carlson and think they know more than medical professionals and then rationalize their avoidance of COVID vaccines? And to what effect?

The Kaiser Family Foundation estimates that from June 2021 through March 2022 about 234,000 COVID deaths could have been prevented had the decedents been vaccinated against the SARS-CoV-2 virus. That protection was especially important during the more deadly Delta virus wave during the earlier stage of the pandemic, but it still extends into the Omicron era, which fortunately is not as deadly as Delta was, but still is not to be taken lightly. People are still dying from the virus.

How does politics come into this?

A 2022 study published in the journal, Lancet Regional Health-Americas, found higher COVID mortality rates in more conservative congressional districts across the US. And in another 2022 study using 2020 presidential election returns, researchers at the University of Maryland and the University of California at Irvine found that, through October 2021, Republican-majority counties across the US experienced nearly 73 additional COVID deaths per 100,000 people relative to majority Democratic counties.

These are correlations looking for a cause. A good causal candidate could be differences in vaccination rates between people who tend toward conservatism vs liberalism. The former are much less likely to get vaccinated than their left leaning neighbors. But, that connection needs to be made.

Sure enough, a July 2023 report by Yale researchers in the journal, JAMA Internal Medicine, compared COVID death rates in counties in Florida and Ohio that voted for Trump vs Biden before and after the vaccines came out. The bottom line was that after the vaccines rolled out, Trump voting counties saw 40% higher fatality rates per million residents. Before the vaccines, the COVID death rates were the same for all counties. Viral infection rates were similar for both types of counties throughout the period of analysis. Importantly, counties and individuals that went for Trump had lower vax rates than those that went for Biden.

That pretty much closes the circle on the causation. The greater reluctance of more conservative people to get vaccinated and boosted likely killed them at a greater rate.

Karma?

Now, don’t get me started on the conservative vs liberal attitudes on face masks and social distancing. Conservatives are wrong on these matters. I say this as a conservative myself. But, I also am a data driven scientist who believes data trumps partisanship.

How do you think SARS and MERS were stopped without a vaccine or anti-viral drugs? How do you think society stopped any epidemic such as small pox, influenza, bubonic plague, etc. throughout its history before modern medicine and effective vaccines? How do you think today we are handling Ebola for which there is no vaccine or drug? Non-pharmaceutical physical measures, like masks, gloves, sanitation, social distancing, etc. are effective ways to halt infectious diseases in lieu of vaccine and drug preventive measures.

Conservative resistance to these non-pharmaceutical physical protective measures also probably contributed to their higher death rates observed in the studies mentioned above.

Karma.


Part 3: Gain-Of-Function Research At The Wuhan Lab—Are The Chinese Hiding Something About The Lab?

This is a re-post of a blog, but with additional material. I added new information about the Chinese government response to the first SARS epidemic. You can find that section two-thirds of the way through the post under the headline in bold "The Chinese have done this before:"

“In a time of deceit telling the truth is a revolutionary act.”
― George Orwell

Yeah, I know, I said this would be a two-blog series about the research at the Wuhan Labs. But a comment a reader made on my second blog post made me think that I should make a third post to briefly address the apparent secrecy and lack of cooperation from the Chinese government regarding the research at the Wuhan Institute of Virology (WIV).

The Chinese have failed to cooperate to help us find the origin of the SARS-CoV-2 virus that caused COVID. They have denied access to WIV lab records or research personnel beyond what was posted on their coronavirus database as I mentioned in my prior blog post. This secrecy and lack of cooperation began in early January 2020 immediately after Chinese officials realized that they had a coronavirus superspreader event at the Wuhan wet market as I described almost three years ago in these pages.

This apparent secrecy on the part of the Chinese has led many people to jump to the conclusion that the Chinese are hiding something sinister—sinister like they secretly created SARS-CoV-2 and accidentally released it and don’t want the world to find out. But, as I have posted several times in these pages, most recently here, there is precious little evidence that supports the notion that the virus came out of a lab. On the other hand, there are several pieces of consistent, but still circumstantial evidence for its natural origin. However, that conclusion is not definitive and could change with new evidence. Hence, we cannot say with certainty that we know where the virus came from. But, remember, it took 14 years and a LOT of work to learn the origin of the virus that caused the first SARS outbreak; it took much longer to discover the source of HIV, and we still do not know where the Ebola virus came from. These things are very hard to learn and take time to figure out.

However, I don’t believe that the best explanation for the Chinese lack of cooperation is that they are hiding something sinister from the world because it seems very unlikely that the virus was man-made. After all, we have several examples of novel coronaviruses popping up in animals and humans, and all have had natural origins. And as I described in my prior post in this series, it is next to impossible that the virus was accidentally released from the Wuhan labs since they really did not work live viruses at all. I think one of two other explanations for Chinese intransigence is more plausible.

The least likely alternative explanation is that WIV lab safety protocols for handling dangerous pathogens were substandard and for the Chinese to allow access to lab records would reveal to the world how careless they were. Perhaps they were concerned about their world image and did not want to be embarrassed. It could deleteriously affect their R&D collaborations with other countries. But, we already had an idea that their safety protocols were not up to Western standards so this would not have been a terribly shocking revelation. That is why I don’t think this is the most likely explanation for the lack of cooperation and transparency.

More likely, however, I think the lack of cooperation probably reflects the general and significant deterioration in science and technology collaboration between China and the US that has been going on for five years. This was the topic of a long article in the Wall Street Journal just a few days ago. In fact, US-China science and tech cooperation has gotten so bad in recent years that US lawmakers are pushing to let a long-standing agreement between the two counties to cooperate broadly on science and technology lapse. It was originally signed in 1979 and renewed every five years since, but will expire this month if not renewed as several lawmakers are pushing.

A once highly productive cooperative science and technology agreement between the US and China seems to have begun falling apart in 2018, before COVID, according to the WSJ article. That is when the US DoJ launched its China Initiative to ferret out Chinese economic espionage. Over time the program increasingly focused on interactions between US universities and Chinese institutions. NIH also launched hundreds of investigations into ties between US science and China. While all these investigations largely failed to turn up criminal conduct, they understandably put a major damper on further cooperation between China and the US. They also led to an exodus of Chinese scientists from American labs. Given all that, it is not surprising that Chinese officials are not opening the doors and books of the Wuhan labs to us.

Thus, this lack of cooperation regarding access to the Wuhan labs is happening as cooperation is seriously deteriorating across the scientific spectrum, not just at the Wuhan labs.

The Chinese have done this before: The Communist Chinese government also has a long history of invoking repressive secrecy in order to prevent itself from looking bad. For example, they also clammed up during the first SARS outbreak back in November 2002 and it threw the country into its worst political crisis since the 1989 Tienanmen Square uprising. The government’s first response to the emerging epidemic was to hide the outbreak from its people, and even from its own public health officers. Despite the cloak of a news blackout, SARS spread throughout the country, reaching Beijing that March (viruses don’t read the newspapers!). But doctors do, and the cloak worked on them. Because of all the secrecy, they were caught by surprise by the sudden and prolific appearance of a new disease, and only learned what was going on via surreptitious text messaging.

In April, WHO officials finally were allowed into the country to inspect Beijing hospitals in order to assess what was going on, but sick patients were shuttled out of the hospitals in ambulances to different hospitals or checked into hotels to hide them from inspectors. Because Beijing tried to hide all this from the world, the epidemic, which might have been limited to that city, found its way into 32 countries around the world (viruses are very slippery). Fortunately, those other countries were not as furtive and were able to nip their infections in the bud with public health measures such as quarantines, contact tracings and isolation, and public closings.

SARS allowed the world to see and compare how repressive and self-sensitive China vs other world countries handle a deadly contagion. China was afraid of losing face and tried to hide its problem from public exposure. However, this backfired and showed China to be a repressive country that was willing to risk the safety of its people and the world in order to avoid accountability for the first SARS outbreak.

Therefore, it is not terribly surprising that the Chinese government again is using repressive means to avoid being put into a position of accountability for the second SARS outbreak.

The bottom line is that to think the Chinese are hiding something nefarious and conspiratorial at the WIV is pure speculation and is backed by no evidence at all. So far. There are alternative explanations for the lack of cooperation by the Chinese that are more feasible and reasonable to believe at this point. New information could change this assessment of course, but evidence that the Chinese are hiding something is lacking. Too bad they won't let us confirm that.

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Part 2: Gain-Of-Function Research At The Wuhan Lab—What Exactly Was The Wuhan Lab Doing With Coronaviruses?

“I’m just a soul whose intentions are good; Oh Lord, please don’t let me be misunderstood.”  —The Animals

In the first part of this two-part blog series, I described what gain-of-function research entails in order to set the stage for this blog post which describes the coronavirus research that went on in the Wuhan labs. So, was it dangerous and risky? Did it likely lead to the release of SARS-CoV-2 that caused COVID? Let me try to clarify all that now.

Coronavirus research at the Wuhan lab: After the first SARS epidemic in China in 2002, the Wuhan Institute of Virology (WIV) had established itself as a world class coronavirus research lab. It was from their diligent work that the world learned that the first SARS virus came from a horseshoe bat via other animals such as civets and raccoon dogs. That was the result of years of arduous research trudging through bat guano muck in hundreds of caves throughout China to collect samples from thousands of bats. They reported their finding 14 years after SARS appeared and shortly after another strange, lethal flu popped up in the Middle East that was soon attributed to yet another bat-borne coronavirus that came via camel intermediate hosts—MERS.

Before these two coronaviruses that jumped from animals to cause significant disease in humans, the viruses were only known to cause mild human maladies; basically, the common cold. Therefore, when it was learned that the deadly SARS and MERS diseases were caused by coronaviruses, it rattled the cages of health experts around the world. This was brand new!

Hence, even before COVID struck, bat-born coronaviruses were hot on the radars of infectious disease nerds and public health worrywarts. The WIV, as one of the world’s preeminent labs for identifying novel coronaviruses was given international funds to continue their efforts to identify and catalog bat coronaviruses. As they did years earlier when they identified the origin of the SARS virus in horseshoe bats, WIV scientists traveled to far-flung Chinese caves to collect bat guano and biological samples (blood, saliva, fecal) from captured bats. The samples were brought back to the lab in Wuhan for analysis.

Since it is exceedingly difficult and potentially very dangerous to grow wild viruses from such samples (failure is the norm even when many viruses are present in the samples) the lab resorted to their previous tried and true methods of searching the samples for viral genome sequences. They found a LOT of new ones!

Their first and primary order of business in this research was the very mundane task to sequence and catalog all the different coronaviruses they found. They then colligated these genomes into trees of different virus families and posted all the data in a vast database for world scientists to use. They were coronavirus genealogists.

The database is an enormously useful research tool for scientists around the world studying the origins and evolution of coronaviruses in animals and humans. (Coronaviruses also cause significant animal disease, so they also are of great agricultural interest around the world.)

The Wuhan lab also was charged with predicting which of the new virus sequences they found might pose future health threats to humans.

This is where all the controversy begins.

Remember that the Wuhan scientists actually did not have these viruses on hand, just their genome sequences. So, without the actual virus, how could they evaluate the ability of new coronaviruses to infect humans? To do this WIV scientist, Zhengli Shi, used a genetic engineering technique first published in 2015 by Univ. of North Carolina Scientist Ralph Baric to study coronaviruses from their genome sequences (she was a collaborator on Baric’s 2015 paper, so was quite familiar with the approach). It was a technique that also was in use at the time by several labs around the world. It is notable that NIH funded this coronavirus research conducted by Baric at UNC well before COVID appeared and didn’t consider it to be GoF research then.

Using Baric’s genetic engineering technique, Shi’s lab at the WIV used as a tool, a benign coronavirus that they could grow in the lab that was only distantly related to the first SARS virus, but was not known to cause human disease. Its genome sequence was not at all related to SARS-CoV-2 that caused COVID, and which had not yet appeared.

Shi’s lab removed the spike protein gene sequence from the genome of this benign lab virus tool and methodically replaced it with spike protein sequences from each new virus they sequenced. They then grew the lab virus tool carrying the new spike protein and tested its ability to infect human cells in tissue culture.

It is the spike protein that determines whether a coronavirus can infect human cells. Therefore, if the chimeric lab virus carrying the new spike gene infected human cells, it would indicate that the virus the spike protein sequence came from was a likely human pathogen and that virus sequence was then listed on the database as a potential human risk. However, if the chimeric test virus failed to infect the human tissue culture cells, that meant that the spike protein from the new virus genome would not support infection of human cells and the new virus sequence was not categorized as a concern for human infection.

This is how newly identified coronavirus sequences were categorized as potential human health threats without ever having to grow or isolate each virus itself.

In other words, this test simply expressed the spike protein of each novel coronavirus on the backbone of the safe lab virus genome in order to see if it could infect human cells. This completely negated the need to grow and handle the potentially much more dangerous wild-type virus.

It is important to notice that this strategy eliminated all risk of a lab leak of any dangerous virus since it was not necessary to grow or handle potentially dangerous wild-type viruses using this technique.

Is this gain-of-function-research? Strictly speaking, no. Remember, this sort of coronavirus engineering research had been done years earlier in Baric’s UNC lab, and was being done in other labs around the world, and it was never regarded as GoF research then by NIH.

NIH considers GoF research on pathogens to be research that either: 1) increases the pathogenicity of a microbe (that is, makes its disease worse), 2) improves its transmissibility or its ability to infect hosts, or 3) alters the host range of a pathogen. Therefore, in the WIV experiments to assess the ability of novel virus genome sequences to infect human cells, the chimeric test viruses that simply expressed new spike proteins on a laboratory virus backbone either retained the ability of the original lab virus to infect human cells, or they lost the ability to infect human cells.

Therefore, the chimeric viruses gained no new function that was tested. They either retained or lost the ability to infect human cells. The experiments were not at all designed to give the test virus any new functions. Furthermore, these experiments could not have led to the development of SARS-CoV-2 that caused the COVID pandemic, even by accident, since the laboratory test virus used to create the chimeric viruses in the experiments was not at all related to the SARS-CoV-2 virus.

There is a devil in the details: But. Notice that one of the the NIH definitions of GoF research is research that alters a pathogen’s host range. For example, take a flu virus that only passes between birds; avian flu. If you make changes in its genome so that the birds can also pass it to humans that mutation alters its host range and is a GoF change.

In the WIV lab, viruses with new spike protein gene sequences were only tested for their ability to infect human cells in a petri dish. The ability of these chimeric viruses with new spike proteins to also infect other animals was not tested. Theoretically, the chimeric test viruses could feasibly also infect, say a water buffalo, or a wart hog, or some other animal that the original lab virus might not have been able to. That would be a technical gain-of-function. But, that begs the question; in such an experiment, how would you know whether or not the host range of the chimeric virus had changed until you possibly had tested its ability to infect every known animal? A logistical impossibility.

Therefore, based on this theoretical point, it cannot be definitely stated that the experiments were not GoF experiments. In fact, chances are pretty good that some of the novel spike protein sequences attached to the lab test virus in fact altered its host range and, thus, the experiments would technically be GoF research.

Bottom line: Technically speaking, therefore, these experiments carried out at the WIV probably could be called GoF experiments. By a lawyer. Not by a scientist. That picks the proverbial nit and splits a very fine frog hair, to mix metaphors. The same research had been done ten years earlier in Ralph Baric’s UNC lab and was not considered GoF then. What is important is that the research at the UNC or the WIV never set out to create viruses with enhanced virulence, transmissibility, or altered host range. That was never the intent. The aim of the WIV research was solely to predict the human risk posed by novel coronaviruses without actually having to directly work with the potentially dangerous pathogens. Actually working with the dangerous viruses would have posed a very real risk.

Bottom, bottom line: The research conducted at the WIV was the most safe and responsible way to identify new coronaviruses that could potentially pose future human health risks. It is to the detriment of human health that this research has come under heavy criticism and that such future research has been hampered by criticism from people who fail to understand what the research is about and have, therefore, demonized it and want to prevent it.

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While SARS-CoV-2 And Our Immune Systems Do A Dance, We Get Re-Infected

Note: Artificial intelligence wrote nary a word of the following article, which was fully composed by the natural intelligence of a certain human.

Your sometimes humble blogger remembers how immunology science first beguiled him. It was during senior year in high school in the Virginia suburbs of Washington, DC. More specifically it was during a lunch break while working at a People’s Drug Store that had a lunch counter. Your then nascent blogger grabbed the recent issue of Scientific American from the magazine rack and opened it to an article that was way above his green scientific understanding but, he, nevertheless, gleaned from the article that the immune system could make antibodies to just about any molecule in the universe, even ones newly created in a lab that the universe had never seen. Amazing!

Your immune system would also make antibodies against the cells and tissues of your best friend and everyone else in the world, and vice versa, but you and your best friend, et al., would not make antibodies against the same cells and molecules in your own bodies! What?

“Holy cow!” I thought. How in the world can the immune system do all that? How can it respond to something the world had never seen and secern friend from foe? At that moment, at that lunch counter over a burger, Coke and an article I barely understood, an immunologist was made. And I did indeed go on to earn a PhD in immunology and I indeed have studied how the immune system recognizes viruses and have done vaccine research. What a pivotal lunch break that was for me.

The question about antibody discrimination clearly fascinated me. That mystery has been solved and a few Nobel prizes awarded for its elegant solution, but related spin-off questions about how antibodies protect us keep coming up in different ways. It did so most recently during the COVID pandemic. Why weren’t the antibodies we generated via vaccination or via natural infection more protective against subsequent infection? In a twist in the plot of biology, it turns out that we have learned that the answers to these questions center around a complicated dance performed between both the virus and immune biological systems.

Biology is so doggone interesting!!

COVID Vaccine generated immunity: The several vaccines we now have against the SARS-CoV-2 virus are effective and provide examples of how vaccines are very good at getting the immune system to respond to what it detects as foreign invaders. But the vaccines are just designed to tell our immune systems to make antibodies against just a very small fragment of the spike protein. In contrast, the virus is constructed of several large proteins each of which has many different regions that the immune system can separately recognize as foreign. In other words, if the virus is like a brick building, your system theoretically can make a different antibody that specifically recognizes each brick of the building. So, the vaccine is like exposing the immune system to about 2-3 bricks of the whole building and trusting the resulting immune response against those few bricks to bring the whole building down.

The immune system was very good in generating antibodies to a small portion of the virus, yet many vaccinated people still were infected and caught COVID. Does that mean, as many vax naysayers claim that the vaccines were ineffective? Not at all, as I have discussed here before. While the CoV-2 vaccines did a good job at protecting against serious disease and death they were not very good at preventing the spread of the virus. These vaccines effectively generated a systemic immune response, meaning that you had anti-viral antibodies circulating in your blood, which did do a very good job preventing serious disease once the virus got inside you. But, it still got inside. You still got infected and got mildly sick.

We now know that the virus enters via mucous membranes in your nose, sinuses, mouth, throat and eyes. It has to first cross mucous membranes in order to infect you and that is where it needs to be stopped in order to actually prevent infection and further spread to others. The problem is that mucosal immunity is caused by a different type of antibody than what circulates in the blood and by what is generated by a typical vaccine that is given by an injection in the arm. To generate mucosal immunity, you need a vaccine that you spray in your mouth or nose, which then should generate the type of antibodies that provide mucosal protection and better protect you from infection via that route and better prevent the virus from spreading through a population.

At the beginning of the pandemic, we were faced with a brand new pathogen for which we knew nothing about how it behaved or how it infected and spread between people. At that point, we reasonably chose to quickly make the most common type of vaccine--a shot. While it didn’t fully protect against getting infected, it nevertheless was very effective at protecting against serious disease. So, it did a good job. Current efforts are underway to develop a mucosal vaccine. But, we must also deal with other complications we have learned about the dance between the virus and the immune system to make sure that vaccine will be maximally effective at preventing infection. Read on.

“Natural” COVID immunity: As it became clear that vaccinated people were still getting infected, the vaccine dissenters and dissemblers proclaimed loudly, and still do, that the vaxes failed miserably. They ignored the survival data and only focused on the infection data. They then began touting “natural immunity,” which is the immunity one usually gains after being naturally infected. But, that can be uncertain given the fact that the route of infection and the dose of virus can vary wildly and confer different levels of protection, as I reported earlier. Plus, with natural infection, one runs the risk of serious disease and death from the disease.

Then, to the chagrin of the “natural immunity” enthusiasts it turned out that they also were getting re-infected! And this re-infection occurs despite the fact that natural immunity occurs after infection across the mucous membranes that should, as discussed above, generate an immune response that would stop an infection! This is the dance.

Therefore, we now know that neither vaccine immunity, nor infection immunity fully protects against future infection with the CoV-2 virus (there is partial protection, but I won’t go into that here).

As we learned as recently as last April, from a Harvard study published in the journal Science, despite the fact that a natural infection presents the immune system with the full viral “building and all its bricks” potentially recognizable by antibodies, it turns out that only a few of the “bricks” are in fact actively “seen” at any time by the immune system.

This immuno-dominance of a small part of a larger pathogen that has thousands of sites or bricks the immune system can recognize is not unusual. It is like a large building consisting of thousands of bricks, but having a very attractive window that draws your attention. While you know an entire building is there, your attention is mostly drawn to the window. So can the focus of the immune system be preferentially drawn to a small part of a larger edifice. The immune system is perfectly capable of seeing the rest of the “building,” but it prefers to direct its attention to a small part of it. However, if you take away the part it prefers to focus on, the immune system will easily recognize something else. This immuno-dominance in what the immune system “sees” has several causes that are way too complicated to go into here without writing a textbook (an interested reader might try Paul’s Fundamental Immunology. My rather old edition of that book runs about 1500 pages!). Suffice it to just know that this sort of immuno-dominance often happens where only a small part of a large pathogen is preferentially recognized by the immune system.

Thus, the immunity developed after a natural infection is mostly only directed at a small portion of the virus, much like the antibody response after vaccination with just a small part of the virus. The natural immune response, like the vaccine immune response, is robust and effective, yet both are only directed against a very small portion of a big pathogen, and both are very leaky in that one can still get infected again! What gives?

Mutation gives.

How the virus escapes immunity: The SARS-CoV-2 virus is highly mutable unlike the other viruses like polio and small pox we vaccinate against and maintain long term immunity against. Thus, the virus quickly mutated, or changed, the “bricks” against which the vaccines were made rendering the immune response less and less effective over time as new viral iterations appeared. That is why the many boosters we got were necessary to keep vaccination immunity up with viral changes.

And that also is how someone who became immune after natural infection also became re-infected. The virus did a two-step and mutated the small region recognized by the immune system. It was pretty easy for the virus to do since it only had to change a couple of “bricks” in its facade that the antibodies were mostly attacking. That means that upon re-infection with a slightly mutated virus, the immune systems have to be re-educated to recognize a new intruder, and that takes time, which allows a new infection to settle in. Thus, in this dance, the gentleman virus leads and the dame immune system follows.

New vaccines continue to be developed that scientists hope will solve these problems unique to SARS-CoV-2. Most of the new vaccines are being built on the mRNA platform, but using novel approaches to 1) develop vaccines that can be given as a nasal spray in order to generate the mucosal immunity that hopefully would be more effective at actually preventing COVID. If this works, it might even be possible to hinder COVID spread. 2) But in order to block CoV-2 spread on a population level, we need to find other regions of the virus that are not so highly mutable. These would conceivably be regions of COVID proteins critical for viral function that tolerate little change in structure because that change would destroy the proteins' critical function and essentially kill the virus. Alternatively, new vaccines could incorporate multiple "bricksl" from different regions of the edifice assuming that it would be nigh impossible for all those sites to simultaneously mutate. If such regions are accessible to the immune system, then the resulting immunity would be expected to be impervious to viral mutation, thus ending the dance on a sour note.

It is even possible that such a vaccine could protect against a wide range of coronaviruses, thereby preventing future health problems arising from new coronaviruses. Remember SARS that also popped up in China a couple of decades ago? That virus has some genome similarity to the virus that caused the COVID pandemic, and both are distantly related to the virus that caused MERS that arose in the Middle East. If a pan-coronavirus vaccine can be developed, it could feasibly prevent many future epidemics and pandemics.

We shall see.

This is all part of a new biology that I earlier dubbed BioX. Biology is so doggone interesting!!

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The Virus Came From Wuhan Lab DOE Now Says…..Sort Of

 Where’s the beef?” Clara Peller in a 1984 Wendy’s commercial

So, the world has been abuzz since the Department of Energy recently reported that it decided, albeit with low confidence, that the SARS-CoV-2 virus might have leaked by accident from the virology lab in Wuhan. Across cable television and the internet, including sources such as Fox, Breitbart, Joe Rogan, gossip lines, et al., are full of “I knew it all along,” and “I told you so’s.” Never have so many virology experts suddenly been spawned on Facebook. And most of them could not tell you whether a coronavirus is an RNA or DNA virus, let alone the difference between RNA and DNA.

But let’s slow down a bit. Have you even wondered why the Department of Energy is releasing an assessment about a virus? And did you wonder what data they based their assessment on? I did and I explain it here. What I learned tells a much more complete, and less compelling story than what most of the priests of the press, Junior virologists, and other rumor mongers have reported. What has been reported has been woefully inadequate and vastly misleading.

The DOE report was based on intelligence data that remains classified, and is not a science report. Apparently intel spooks weigh science information much differently than scientists do, and often put less credibility in published science because the information usually does not come from “trusted” sources that an spook has history with (their version of "peer review" I guess). The US intelligence community is distributed between 18 agencies, including Energy, State, Treasury, and others including, of course, the CIA, FBI, and DOD. Eight of these entities have been involved in reviewing the COVID-origins issue.

In 2121, the Energy Department, which oversees 17 national laboratories, several of which study SARS-CoV-2 and its origins, reported it was undecided on how the virus emerged. What caused DOE to recently change their assessment is not known. They are not releasing the classified data. Therefore, their information appears not to be scientific data, which is usually published. Four other unnamed agencies, along with a national intelligence panel, still judge that the virus was likely the result of a natural transmission from an animal to humans, and two other agencies are undecided. Only the FBI agrees with DOE in thinking that the virus leaked from the lab. Notably, the CIA also remains undecided. In other words, the DOE’s opinion is a minority opinion of low confidence in the intel community. It is hardly worth all the breathless excitement it elicited from Tucker Carlson and other bloviators who now dishonestly insinuate that it has now been proven the virus came from the lab. That is far from decided.  

The intel community’s definition of low confidence intelligence is “that the information’s credibility and/or plausibility is uncertain, that the information is too fragmented or poorly corroborated to make solid analytical inferences, or that reliability of the sources is questionable.”  Someone should send that to Tucker.

The origin of the virus has been actively investigated over the last couple of years and your sometimes humble correspondent has reported previously on those investigations in these pages (it is worth reading for background). These blog posts have favored the natural origin of the virus, because that is what the preponderance of data have suggested. There have been no published data supporting a lab leak hypothesis. None. Also, recent science reports in top-flight science journals continue to conclude that the virus had a natural origin. A paper just published in 2023 in Cell reported that SARS-CoV-2 is the ninth known coronavirus to have jumped from an animal into humans. Two earlier reports in Science, and also summarized in these pages last March, agreed that the virus originated in the Wuhan wet market not just once, but twice. These studies included genetic evidence and epidemiological tracing showing that the early cases of COVID all centered around the Wuhan wet market and not around the lab eight miles away.

Furthermore, back in 2020, I also wrote a summary of how the earliest events of the pandemic unfolded. Here is a synopsis of the first few days: On December 31, 2019, Chinese officials informed the WHO about a cluster of 41 patients with a mysterious pneumonia in the city of Wuhan associated with a new coronavirus. Then, in the middle of that night a Chinese CDC team from Beijing arrived and collected 585 “environment” samples from a garbage truck, drains and sewers in the wet market. Thirty-three of the samples tested positive for the new coronavirus. Fourteen of the positive samples were from the area of the market where wildlife was traded. At the same time, Wuhan officials quietly began disinfecting the market, and it was closed.

It is interesting that the immediate focus was on the market and not the lab.

Keep in mind that we have very many examples of viruses, including several other coronaviruses similar to SARS-CoV-2, spontaneously passing from animals to cause disease in humans. This includes the first example of SARS-CoV-1 that came from a food market in China in 2002, and then MERS, which passed from a camel to humans. It was natural for medical scientists to first think that SARS-CoV-2 arose similarly. So far, the evidence is not convincing that it did not. The fact that we have not yet convincingly identified an animal source for the virus is not surprising. It took 30 years to establish the source of the HIV virus, and we still do not know the source of the Ebola virus.

So far, despite the very weak statement from the DOE, the preponderance of data still favors a natural origin of the virus, not a lab origin. But, that still is far from definitive. That “preponderance” of evidence, can change in a hurry with new data. Therefore, it remains worth further investigation. But until the Chinese government allows outside scientists to review lab data books and interview scientists from the Wuhan labs, the investigation will proceed with one hand tied behind its back. It remains remotely possible that an animal carrying the ancestral coronavirus will be caught confirming that it did come from an animal. Yet, even if we did find an animal source for the virus, it may not tell us about the path it took to get into humans. We might never know that to the delight of the conspiracy nuts and fabulists out there who have never weaned off the teat of fantasy.

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The Latest On Long COVID (So Far)

“After all, tomorrow is another day.” Gone With the Wind

In these pages, your humble bloggeur (me) has followed the evolution of what we know about the odd condition known as long COVID. You can find seven previous blog posts on the topic here. Because we were just learning what long COVID was all about, many of those posts ended with the disclaimer, “we will see.”

Well, we have seen and continue to see. Here is what we now know after over 2 years of experience with this complication. But, tomorrow is indeed another day.

The risk of death from COVID is now about the same as the risk of death from flu, which can vary from year to year, thanks to vaccines, natural exposure, and developing therapies. One study in Lancet found that people with COVID had a 3-fold greater chance than uninfected people of dying each year. But, as I explained before, mortality is only part of the story. There also is morbidity. Long COVID is "the rest of the story" as Paul Harvey used to drone. Some 54 studies on long COVID, involving 1.2 million people, have been reviewed and it was reported that about 6% of people with symptomatic COVID infection wind up with long COVID. This agreed with a massive Swedish study of COVID patients done between 2020-21. According to the new Census Bureau Household Pulse Survey, some 16 million working age Americans now suffer from long COVID, which creates a huge burden on our health system. Up to 4 million of these are unable to work, which is a major drain on a labor market already short of workers. The annual cost in lost wages is up to $230 billion! The total economic cost of long COVID in the US so far has been an astounding $3.7 trillion!!

And as the virus evolves, reinfections with new CoV-2 variants are becoming more and more common. Unfortunately, a large VA study on reinfections suggests that you want to avoid them. A second or third infection is associated with worse disease and increased chance for long COVID. And a large German study including nearly 12,000 children with COVID concluded that long COVID “cannot be dismissed among children and adolescents.”

A sobering study of medical records from millions of US military veterans in the VA medical system published in Nature Medicine found that 7% more COVID patients (compared to uninfected veterans) had lasting brain or neurological disorders. This extrapolates into about 6.6 million Americans with long-term brain impairments linked to COVID. Memory impairment was the most common brain malady. But those with a history of COVID also were at greater risk of ischemic stroke, seizures, anxiety and depression, and movement disorders.

The good news is that vaccines reduce the risk of long COVID—how much is still debatable at this point. The anti-COVID medicine, Paxlovid, reduces long COVID risk by 25% according to one study. And the Omicron CoV-2 variant shows a reduced risk of long COVID compared to the more pathogenic Delta variant.

Assessing the risk: How much should the risk of catching long COVID affect one’s daily decisions? Should I go to the concert? Graduation? Grocery store? Wear a mask everywhere? That is hard to say definitively. Perhaps it would help to compare COVID risk to other risks we face every day.

  • The annual risk of getting in a car accident is about 1 in 30 per year. Of those, ~43% involved injuries and ~10% of those cause permanent impairment. This makes the annual risk of permanent injury from an auto accident about 1 in 700.
  • The annual risk of serious injury in a house fire is ~1 in 20,000.
  • The risk of needing reconstructive surgery after a dog bite is 1 in 400 annually.
  • The risk of catching the Omicron variant (symptomatic or asymptomatic disease) is ~1 in 2 annually (it was 1 in 4 before Omicron). Say 3% of those get long COVID, and ~18% of them are so sick they are unable to work for an extended period. This makes the annual risk of severe long COVID about 1 in 370.

So, the risk of debilitating long COVID is about twice the risk of serious injury from driving and about the same as getting a serious dog bite. The risk of severe long COVID is much higher than being injured in a house fire. Of course, all of these risks are affected by our personal behaviors. We don’t drive drunk and wear seat belts (hopefully). We replace the batteries in home smoke detectors every year and avoid growling curs. And if we are smart, we vaccinate and stay home when we are not feeling well.

At least those are things that responsible people do to reduce the risks of life.


Are COVID And Cancer Connected?

Nothing surprises me, I’m a scientist.” 

                            -Indiana Jones   

In 2019, the world was introduced to a brand new pathogen, the SARS-CoV2 coronavirus, that caused a brand new, and very odd disease, COVID-19. Between then and now, your humble bloggeur has penned 153 blog posts, many of which focused on how strange the disease is and describing our learning process as we figured it out on the fly. Many of these posts were necessarily equivocal because we simply did not have enough information to make firm conclusions on how the virus affects different people. Over time, we learned how to better treat the disease, and that learning curve continues. It was necessary to end many blog posts with the weak statement, “We will see.” Well we are still seeing and learning about this odd malady that consists of a melody of symptoms across myriad organs.

Research is now beginning to reveal a possible link between CoV-2 infection and cancer. As before, these observations are preliminary and will be further scrutinized, but they are bolstered by the discovery of a possible mechanism that could explain how the CoV-2 virus might cause cancer.

We know of many different viruses that cause cancer in animals. We also have a good understanding of how the viruses do that. There also are a few viruses, but not many, that cause human cancer, and we also mostly understand how they exert their oncogenic effects. These human cancer viruses include human papilloma virus (HPV), which causes cervical, and head and neck cancers. Hepatitis B virus can lead to liver cancer. Human T cell leukemia virus causes leukemia, and Epstein Barr virus can lead to lymphoma and a few other types of cancers. And so on.

To date, there has been very little association between any coronaviruses and cancer in animals or humans. But, that might be changing.

Several recent papers have revealed a genetic link between COVID-19 and cancer. One paper showed that people with an increased genetic risk of COVID-19, were also at increased genetic risk of developing endometrial cancer. The limitation of this study is that it cannot distinguish between a correlated high risk of COVID and cancer, vs whether COVID causes the cancer. It is the old conundrum of discerning between correlation vs cause-and-effect.

A second study incrementally advanced the above findings. Using a low resolution genetic mapping technique called genome-wide association, it found a positive correlation (there is that “C” word again) between people genetically predisposed to both severe COVID and increased risk for endometrial cancer. While still a correlation, one would predict that if there was a cause-and-effect relationship between COVID and cancer, that the risks for both would be similar. This is what the study showed.

Finally, a third study uncovered a possible mechanism by which SARS-CoV-2 could cause cancer. Having a possible mechanism in hand bolsters the possibility that the theoretical link between COVID and cancer is true. But first, a little back story about cancer genetics.

Cancer genetics.  Basically, cancer is a genetic disease. That does not necessarily mean that it is always inherited. Most cancers probably are not. But, when the genetic fidelity of a cell messes up, it can become immortal, can grow in an unregulated fashion, and can become resistant to normal signals that should cause it to die. In a nutshell, that is cancer. Generally speaking, there are two kinds of genes that contribute to this process. 1) Dominant acting oncogenes are aberrant genes that when expressed, drive the above activities. 2) Suppressor genes provide brakes to the above activities, and when absent, the brake is released. In both cases, genetic abnormalities either activate oncogenes to drive cell immortality and growth, or eliminate expression or activity of tumor suppressor genes removing the brakes to cell growth. Usually, cancer is a stepwise process in which cells sequentially accumulate different abnormal oncogenes and suppressor genes. The combination of which leads to full blown cancer.

One of the first tumor suppressor genes to be identified is called P53. In several different tumors, it was noticed that expression of this gene was missing due to DNA mutation. Further research showed that when expressed, P53 provides a brake on cell growth. There are many ways that P53 can be inactivated. Genetic mutation can prevent its expression, or hinder its function. We also know that a few viruses that cause cancer in people, like hepatitis B virus and Epstein-Barr virus, produce proteins that can interact with and inactivate the P53 gene product. A paper published in November, now reports that two CoV-2 proteins interact with cellular proteins to stimulate complex pathways that lead to degradation of the P53 gene product, releasing the anti-cancer brake in infected cells. The research also shows that that P53 activity is lost in patients with severe COVID disease but not in those with less severe illness. P53 loss also correlates with length of COVID symptoms. In other words, the more severe the COVID disease, the greater the chance that the P53 brake is lost.

This observation does not yet prove that inhibition of P53 by the CoV-2 virus causes cancer, but it now presents an important hypothesis that will be given much research attention. Questions remain regarding the association between CoV-2 infection and cancer. Also, since COVID infections are generally relatively short-lived, how long does the loss of P53 function last? Are long-COVID patients at increased risk for chronic loss of P53 and cancer? Is this loss of function sufficient to launch the multistep pathway that leads to cancer?

Once again, we will see.


The Next Pandemic Is Here

Who ya gonna call?  --“Ghostbusters”

We seem to have mostly weathered two-plus years of a pandemic like the world has not seen in our lifetimes. It raced across the globe killing and maiming people, and overwhelming health care capabilities. Sure, we have read the history about the black plague, small pox, and the Spanish flu pandemics, but vicarious experience through books and film is no substitute for first-hand experience. We now have that experience. It was sobering to see the novel SARS-CoV-2 virus ravage country after country while medical experts played a desperate game of catch-up to learn how to retard the spread of a brand new virus and how to treat the brand new COVID-19 disease it spawned. It was sobering seeing and hearing about people we know get very ill and sometimes die, and sobering reading the statistics of millions of deaths that occurred worldwide.

While most of us today have not seen such a pandemic wild-fire before, we have seen other, more smoldering pandemics that do not spread as fast. HIV is a good example. It too is a world-wide disease that, for many years was a death sentence for those who were infected. Now it is a well-managed chronic disease, thanks to medical science.

The world was not as frantic over HIV and AIDS as we were over CoV-2 and COVID. The reasons for this are probably two-fold: First, it was quickly recognized that AIDS was largely limited to homosexual men and IV drug users and, therefore, was not an eminent threat to most of us. It was not necessary to quarantine, mask up, and shut down businesses and schools in order to prevent catching the “gay disease.” Second, despite the world-wide spread of AIDS, it is not easy to catch. You must be in very intimate contact with an infected person to catch it—it is not caught by simply breathing the same air as an infected person like COVID is. Clearly, not all pandemics are created equal. Some smolder like AIDS, others fulminate like COVID. What will our next pandemic be like?

As the global population grows, as the climate changes, as humans push into spaces occupied by wild animals, and as we continue enjoying our ever increasing global connectedness, future pandemics become more likely. We are not guaranteed the luxury of facing just one a century, or even one at a time. As greatly encouraging, even exciting as it was to watch the post-molecular BioX science, as I have called it, roar into life to produce several effective and novel anti-CoV-2 vaccines in record time, there is no guarantee BioX can save us next time.

Well, the “next pandemic” already is upon us and BioX is struggling to deal with it. This pandemic is not as volatile as COVID or the Spanish flu. In fact, compared to COVID, it is a “slow mo’” pandemic, more like AIDS. But, it promises to be more difficult than COVID, even for BioX, to mitigate. It currently kills about 700,000 people annually around the world, but threatens to kill 10 million people a year by 2050 (in contrast, COVID killed ~6 million around the world in 2.5 years).

The problem

 In March 1942, Anne Miller of New Haven, Connecticut, was near death. A bacterial infection had made its way into her bloodstream, which was a death sentence at that time. Desperate to save her, doctors administered an experimental drug called penicillin, which Alexander Fleming accidentally discovered 14 years earlier. In just hours, she recovered, becoming the first person to ever be saved by an antibiotic. Rather than dying in her thirties, Mrs. Miller lived to be 90 years old and Fleming went on to win the Nobel Prize for his inadvertent discovery.

Today, decades later, germs like the one that infected Mrs. Miller, but easily eradicated with antibiotics, are increasingly becoming resistant to penicillin and the many other antibiotics that have since been developed. There is a very good chance that right now, you have such a “superbug” in or on your body—a resistant germ that, given the opportunity could enthusiastically sicken you leaving medical people at a loss on how to treat you. You would be at the mercy of the bug just as all patients with a microbial infection were before Mrs. Miller.

We are not talking about a new, exotic germ like CoV-2 suddenly appearing and ravishing the world. The antimicrobial resistance crisis stems from the simple fact that new antibiotic development cannot keep pace with the rate that common microbes become resistant to antibiotics. This very slowly growing pandemic we are now in involves run-of-the-mill pathogens, bacteria and fungi that have caused disease since humans first dragged their knuckles on the earth. These are bugs which we had well controlled with antibacterial and antifungal drugs, but there is a very definite trend toward these germs becoming resistant to ALL known antimicrobial medicines we have. Infection with multidrug resistant pathogens is the slow moving pandemic that already is among us but that is growing at a logarithmic rate.

Since multi-drug-resistant infections do not respond to our antibiotics, treatment increasingly involves surgically removing an infected organ. For example, in the case of drug-resistant Clostridioides difficile (aka, “C-diff) colitis, an emergency colectomy is performed when patients no longer respond to antibiotic therapy. CDC data show C-diff infections occur in half a million patients each year, and at least 29,000 die within one month of initial diagnosis. Up to 30% of patients with severe C-diff colitis develop sepsis require emergency surgery, and still their mortality remains high.

As of 2019, about 18 drug resistant pathogens affected >3 million people in the US, causing 48,000 deaths. These bugs cause pneumonia, septic shock, various GI problems, STDs, urinary tract infections, typhoid fever, TB, and infection with the so-called “flesh eating bacteria.” Compared to COVID, this has received relatively little attention in the popular press, but has been a frequent topic in medical lectures and conferences for the last 20 or more years. These infectious disease lectures tend to scare the bejeebers out my colleagues and me. This smoldering pandemic is that serious.

And it is not just antibiotic-resistant bacteria we have to worry about. Certain fungi, especially of the Candida genus, cause various serious ailments in people. Recently, for the first time, the CDC reported five unrelated cases (two in DC and three in Texas) of people infected with fungi that showed “de novo” resistance to all drugs. Usually, drug resistant fungi only appear after infected patients have been treated with antifungals. But, the patients in these five de novo cases had no prior exposure to antifungal drugs. The fungi were already drug-resistant when they infected the patients; they were picked up from the environment already resistant to our medicines.

Antibiotic resistance is now one of the biggest threats to global health. It occurs naturally in naturally occurring pathogens, but is accelerated by overuse of antibiotics in humans and animals, especially farm animals. What happens is that upon treatment with an antibiotic, a single infectious bug out of a population of millions or billions fortuitously mutates and becomes resistant to the antibiotic. The antibiotic then kills off all the non-resistant population, including beneficial bacteria, opening the door for the drug-resistant pathogen to take over. This resistance can occur via many different mechanisms. The bacteria or fungal cell can stop taking up the drug, it can spit out the drug if it is taken up, it can neutralize the drug once it takes it up, or it can change its internal machinery so that it no longer responds to the drug. This problem can be further exacerbated since bacteria and fungi can pass along their mutations by sharing mobile genetic material with their progeny and even with other bugs in their immediate environment that have never been exposed to the antibiotic. They can even pass along this DNA to microbes of different species. Bacteria can also pick up DNA remnants left over from dead germs. Thus, DNA that confers resistance to anti-microbial drugs can spread to the environment even in treated human and animal waste contaminating lakes and streams and ground water.

Currently, the major problem with drug resistant infections occurs in in-patient clinical settings—perhaps you have seen the heightened infection control efforts (gowns, gloves, masks, and isolation) in hospitals designed to prevent the spread of untreatable pathogens. People receiving health care, especially those with weakened immune systems, are at higher risk for getting an infection. Routine procedures, such as bladder catheterization or kidney dialysis are common ways to introduce drug resistant germs into clinical patients. But, infection can happen in any surgical or invasive procedure. Treatment of diabetes, cancer, and organ transplantation can weaken a person’s immune system making them even more susceptible for infections that either are, or that can become drug resistant.

But, antibiotic infections can also occur in the community outside of clinical settings. There is the case of Mike who needed a month long hospital stay for kidney failure after bringing home a new puppy from which he caught a multidrug-resistant Campylobacter infection. He was one of 113 people across 17 states who was part of an outbreak linked to pet store puppies. He recovered after surgery to remove a dead section of his stomach.

+++

The NIH Hospital Experience. About 10 years ago, the NIH Clinical Center in Bethesda was hit with an epidemic of drug resistant infections that killed a number of patients in just a few months. It was such an intractable problem that NIH finally had to gas rooms with a disinfectant, rip out plumbing, and build a wall to isolate infected patients. Still, over a period of six months it reached 17 patients, 11 of whom died. In this case, the bug was Klebsiella pneumoniae, which arrived in June 2011 with a 43-year-old female lung transplant patient who had just transferred from New York City. NIH nurses noted something startling in her chart: She was carrying an antibiotic-resistant infection.

Desperately trying to contain the superbug before it could spread, the NIH staff quickly isolated the woman in the ICU. Staff members donned disposable gowns and gloves before entering her room and her nurses cared for no other patients. After a month, the patient was discharged and the staff believed that their containment measures had worked. There were no signs that the bacteria had spread. But a few weeks later, they were shocked when a second patient tested positive for resistant Klebsiella. A third and fourth soon followed and all these patients died.

This pattern was baffling since, if the bug had not been cleared, it should have reappeared sooner. Even though it was the same type of bacteria, K. pneumoniae, perhaps it had spontaneously arisen anew in the other three patients. But by reading the genomes of the bacteria isolated from each patient, including the NYC transfer, scientists at NIH’s National Human Genome Research Institute saw that the bacteria in the subsequent patients came from the New York patient.

That meant two unsettling things: The bacteria lingered for weeks unnoticed in the hospital environment; and the hospital’s infection control measures for the New York patient failed. A further search for the bacteria found it on a ventilator that had been bleached twice. They also found it in a sink drain in a patient’s room, so they tore out all the plumbing. Yet, it began popping up it in more patients, at a rate of about one per week.

As hospital staff desperately raced to stanch the outbreak, they also struggled to treat the infected patients. Out of desperation, doctors battling the deadly, drug-resistant superbug turned to colistin, an antibiotic of last resort. It is not a new drug, having been discovered in 1949 in a beaker of fermenting bacteria in Japan. It had quickly fallen out of favor then since it causes significant kidney damage. The fact that the doctors resorted to such an old, dangerous drug highlights the lack of new antibiotics coming out of the pharmaceutical pipeline even in the face of a global epidemic of hospital-acquired bugs that quickly grow resistant to our toughest drugs.

While colistin defeated the superbug in a few patients, in at least four, the bacteria evolved so rapidly it outran colistin, too. Those four died. This was when the wall was built and all new Klebsiella-positive patients were moved into a new isolation unit behind the wall. Blood pressure cuffs and other normally reusable gear were tossed after one use. Clinical monitors were hired to follow doctors and nurses around to ensure that they were donning gowns, gloves and masks, and scrubbing their hands after seeing each patient.

+++

Among the most concerning mutating bacteria are carbapenem-resistant Enterobacteriaceae (CRE). Enterobacteriaceae are a large family of more than 70 bacteria that includes the common E. coli, that normally live in the digestive system and help digest food. But, if conditions allow the bacteria to leave the digestive system, they can cause serious disease that needs to be treated with antibiotics. They too can quickly develop resistance to front-line drugs and become a serious problem.  Carbapenem is an antibiotic "drug of last resort" used to treat disease caused by bacteria resistant to other front line antibiotics. Therefore, CRE are resistant to all or nearly all antibiotics and kill up to half the >13,000 patients who get bloodstream infections from them. The CDC first detected this type of antibiotic-resistant bacteria in 2000. Since then, it has been reported in 41 states. In the 10 years between 2001 and 2011, the percentage of Enterobacteriaceae resistant to antibiotics increased almost fourfold according to the CDC. Recently, the CDC tracked one type of CRE from a single health-care facility to facilities in at least 42 states.

The cause

The antimicrobial resistance crisis stems from the simple fact that new antibiotic development cannot keep pace with the rate that bacteria become resistant to antibiotics. Between 1945 and 1968, drug companies invented 13 new categories of antibiotics. Between 1968 and today, just two new categories of antibiotics have arrived. In 1980, the FDA approved 4-5 new antibiotics a year, but now only about 1-2 new drugs are submitted annually for approval. Hence, the solution appears quite simple: Develop more novel antibiotics. However, this is quite complicated since BioX science, which led to the rapid development of the novel mRNA anti-COVID vaccines, has not quite caught up to novel antibiotic development. There are two general reasons for this. First, finding a drug that disrupts the metabolism of bacteria or fungi, but that does not interfere with mammalian biochemical pathways is a difficult and narrow path. Second, so far, the market for novel antibiotics has been comparatively small, meaning that the profit incentive for pharma companies has not been large compared to that for so-called lifestyle medications. While a new antibiotic may bring in a billion dollars over its lifetime, a drug for heart disease may net $10 billion. Drugs to treat depression and erectile dysfunction are typically taken for years making them much more profitable than antibiotics that are used short-term.

Development of bact resistance

Even if we could develop new antibiotics faster, their overuse is the primary driver of antibiotic resistance. According to the CDC, in 2018 seven antibiotic prescriptions were written for every 10 Americans. Of these, one-third were unnecessary, and very often were prescribed for viral illnesses that do not respond to antibiotics. Clinicians writing these prescriptions argue that the antibiotic can help prevent the primary viral infection from leading to a secondary bacterial infection. In other words, many antibiotics are prescribed for prophylaxis rather than treatment.

Time to resistance

The number of new antibiotics that the FDA approves annually has slowed to a trickle, while the rate of bacterial mutation has grown exponentially. It used to take 21 years on average for bacteria to become resistant when antibiotics were first used. Now it takes just 1 year for bacteria to develop drug resistance because antibiotics are so readily prescribed and used. Today, the CDC lists 18 different types of antibiotic-resistant bacteria, five of which are classified as urgent threats to human health.

Physician-prescribed antibiotics, however, are not the only, or even main, source of our antibiotic resistance crisis. In the U.S., 70%-80% of all antibiotics are given to animals, especially farm animals destined for human consumption.  Drug-resistant pathogens from farm animals can spread to the environment providing a gateway through which drug resistant germs can quickly spread across our communities, food supply, and even our soil and water around the world.

Surprisingly, antibiotic use is even rampant in salmon and other fish farms, which is especially concerning, considering that 90% of fresh salmon eaten in the U.S. comes from such farms. Antibiotic-resistant infections also affect petting zoo animals, which can then transfer the germs to people.

The solution

Antibiotics clearly have been miracle medicines, saving countless lives; however, anytime they are used, they drive the development of antibiotic resistant pathogens that ultimately defeat their purpose.  Developing new antimicrobial drugs to counter the growing resistance to current drugs is not working; it is not keeping pace with the appearance of new antibiotic resistant germs. Without drastic changes in the science and economics behind antibiotic development and business, this will only be a partial solution to the growing pandemic. However, what we can do now is resort to low-tech, less expensive, and more innovative mitigation measures. These include alternative prevention steps such as more judicious use of antibiotics and increased use of isolation and sanitation measures (where have we heard this before?). Isolation and sanitation defenses against infectious diseases have been part of our disease fighting repertoire since the earliest awareness that contagions can spread through communities. It is an ancient remedy, but still the most effective way to protect ourselves against contagious diseases worldwide. Between 2013-2019, these mitigation measures led to an 18% reduction in US deaths from drug resistant infections. It always is better to prevent than treat.

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Alternative medical treatment and prevention options.  Besides the obvious masks, gloves, sanitation, and quarantine measures, there are other alternative medical (i.e., non-antibiotic) options that can be used to prevent and control drug resistant infection. In fact, these methods are often preferable to using antibiotics, which also deplete the microbiome of “good bacteria” that are critical for good health. These options include vaccines, therapeutic antibodies, and bacteriophages.

From 2000 to 2016, members of the WHO increased the use of the pneumococcal vaccine around the world, thereby decreasing antibiotic use which slowed the development of antibiotic resistant S. pneumoniae saving ~250,000 children from death. Pneumonia caused by secondary infection with other bacteria is a leading cause of complications and death in patients who get the flu. Therefore, the influenza vaccines also are effective tools to decrease the risk of drug-resistant bacterial pneumonias by preventing viral influenza. Since patients with COVID can also develop secondary complications from bacterial pneumonia, COVID vaccination now is another important weapon in the arsenal to prevent the development of antibiotic resistant bacterial lung infection.  

In recent years, healthcare providers also have been increasingly using therapeutic antibodies to treat viral and bacterial infection. For example, antibody therapy is often used to treat recurrent C-diff GI infections, and antibodies to prevent and treat bacterial associated pneumonia also are being developed. So far, we have not seen bacteria develop resistance to antibodies.

Finally, a different and very novel approach to dealing with untreatable bacterial infection has recently taken advantage of bacteriophages, which are viruses that can specifically infect and kill bacteria. There are a few cases in which phage therapy has been used to cure people dying of multidrug-resistant bacterial infections.  According to Pew Charitable Trusts, as of June 2019, 29 non-antibiotic products like therapeutic antibodies and phages were in clinical development and seven were in Phase 3 clinical trials. 

Perhaps BioX is indeed coming to rescue us from the growing pandemic of drug-resistant pathogens.

Notes: 1) By way of disclaimer, your correspondent has consulted for a biotech company that engages in “big genome” research to search for novel antibiotic molecules produced by everyday bacteria and fungi that grow in the soil under your feet. Something like this could be part of the future of novel antibiotic development. 2) In order to have blog updates delivered to your email, see the simple Subscription Instructions here. Remember, you can easily unsubscribe when you want. But, you can’t beat the price.