Pandemic Pandemonium: Fight Fear with Facts

About Viruses

We have the power to cut through the chaos of a confusing world awash in social media misinformation, breathless hype and ever-more-bizarre conspiracy theories. We simply need to take a collective deep breath and fresh look at this frightening pandemic from a new angle. We can find solace, and answers, in the comfort of basic science and the purity of objective truth.

The pandemic is caused by a type of virus; so, let’s start there.

Viruses are the most reduced forms of life, yet they are nevertheless wondrously complex. In the world of biology nothing is simple, even life in its simplest form. All of us know this intuitively from our own experiences with the flu, a wily adversary that seems to best us every year in spite of global efforts to fight the disease. The flu provides us with salient lessons that we can later apply to the pandemic. The basics, which apply to all viruses, start with how rapidly a virus can spread (pathogenicity). From there we can launch into the other important attributes of a virus that will help us understand the challenge we face today.

Pathogenicity describes how easily a germ (bacteria or virus) causes disease, and how readily it spreads. If just one exposure to a few germs makes someone ill, that bug would be considered highly pathogenic. In popular use we often describe a pathogenic bug as being contagious — that is, the virus or bacteria readily causes disease and easily spreads.

Virulence measures how severe the symptoms are once somebody gets sick. In the most extreme examples of virulence, infection often leads to death. In that case we also discuss a bug’s lethality — which describes how many people who contract the disease die from it.

With those two primary characteristics of pathogenicity and virulence we have four significant possibilities when we encounter a new bug, in order of most to least dangerous:

1. highly pathogenic and highly virulent
2. highly pathogenic and mildly virulent
3. mildly pathogenic and highly virulent
4. mildly pathogenic and mildly virulent

Category 1 would be what happened in 1918 with the Spanish flu. Millions got sick, and of those, 60% died from hemorrhaging, dehydration, fever or massive organ failure. Something like 30–50 million people died from this flu (the statistics are difficult to come by).

Category 4 would describe a virus that slowly spreads through the population, causing mild symptoms such as aches, a runny nose and sore throat. Typical of the cold season.

SARS-CoV-2, the virus that causes the disease COVID-19, falls between those two examples, best described by Category 2: a bug that is highly pathogenic (contagious) but mildly virulent — mild only in the comparative sense that a small percentage (3% or less) die from infection rather than 60% as with the Spanish flu. Don’t misunderstand, 3% represents a large number of deaths — just not as many if 60% of those infected died.

Note, with appropriate horror, that a virus in Category 2 can easily slide into Category 1 with only a tiny mutation. That is precisely what happened with the Spanish flu, which mutated from a common H1N1 influenza A virus (now known as the classic swine flu). In fact, the first wave of the pandemic caused few deaths. Then in the summer of 1918, the flu mutated to become extremely virulent and lethal.

Mutation and the Origins of the Pandemic

How did the Spanish flu mutate from benign to deadly? The answer comes from the process by which viruses replicate. How we name viruses will help tell the story.

Influenza viruses come in three flavors, named cleverly Types A, B, and C. Type C causes disease with mild symptoms. Type B can cause serious illness, but this type of virus has never caused a pandemic. That prize goes to Type A, the source of all flu pandemics past and present.

During flu season or during an outbreak of a particularly nasty Type A flu, we hear in the news jargon like H1N1. What does that mean? Type A influenza viruses are coated with two particularly important classes of proteins: hemagglutinin (the H in virus names) and neuraminidase (the N in virus nomenclature). There are 18 varieties of H and 11 versions of N. So H1N1 simply means that the virus coat is presenting itself to the world by showing version 1 of hemagglutinin and version 1 of neuraminidase.

Every flu virus has some unique combination of H and N; the myriad possible combinations give us 131 different sub-types of Type A found in nature (out of a theoretical 198 possibilities). It is this unique combination that determines a virus’s pathogenicity and virulence.

Every Type A influenza virus is found in wild birds — they are all bird flu. But depending on the H-N combination, some more readily than others jump to other animals like pigs, bats, horses or people.

Now here is the frightening part, the part that explains deadly mutations. A bird (call him Apollo) is infected with a Type A virus that does not infect humans, but can infect pigs (quite typical). Then we have a nearby human (Brad) infected with another common Type A flu virus that can infect people, but pigs as well. In this case, Brad’s virus causes only mild disease but is highly contagious. Sharing the space with Apollo and Brad is, you guessed it, a pig (Hamlet). Living in close quarters with pigs is common throughout much of Asia — and pigs turn out to be a perfect mixing pot for viruses. Hamlet gets infected with the viruses from both Apollo and Brad.

Because of the way viruses replicate, Hamlet’s infected cells will contain gene segments from the viruses from Apollo and Brad. Within Hamlet’s infected cells, the virus genome fragments can recombine to create a brand-new virus with a new combination of N and H. Unfortunately for us, this new combination can take the worst of the lot and be highly virulent and highly contagious — and easily infect humans, even if the original viruses were more benign. We are off to a new pandemic with a highly contagious virus with a new combination of H and N to which nobody has immunity.

What we just described pertained to influenza viruses. But the analogous process can happen with other viruses, like the coronavirus, which is also commonly found in humans and animals (bats mainly, but also in dogs, chickens, cattle, pigs, cats, civets and pangolins). As with the flu, various mechanisms allow different coronaviruses sharing a host to recombine genome fragments to create novel combinations; some of which can be deadly to humans, as we are now witnessing.

That possibility of swapping gene fragments is why we really want to tamp down SARS-CoV2. The virus is causing havoc with a death rate of 3% (perhaps less). Imagine what the world would look like if SARS-CoV2 mutated in a pig or bat or pangolin to become highly virulent, killing 5 or 10 or 20 percent of those infected. The longer the virus circulates, and the wider its distribution, the greater chance we have of such a terrible mutation.

Given the history of Spanish flu mutations, and now the rapid spread of SARS-CoV2, denials of the pandemic are as maddening as they are untethered from the harsh realities of basic biology. Conspiracy theories that minimize the consequences of the pandemic are risking lives. Any calls to relax standards for social distancing are extraordinarily dangerous. Not only are we fighting the current outbreak; we have to be concerned that the longer the virus circulates, the more opportunity for a mutation that will change our world forever. Until a vaccine is available, vigilance is the only option. The only prudent course of action is to flatten the curve until a vaccine becomes available.

Cures for the Pandemic

Along for the ride with wild theories fueled by social media are home remedies for curing or preventing COVID-19. They are as tenacious and as irritating as a remora attached to a hapless shark. The fact is that Uncle Bob, your neighbor Flo, or the latest internet craze are not good sources for medical advice. To debunk the growing number of bogus claims, to truly understand deep down why these remedies are useless at best and often dangerous at worst, we need to delve into the world of drug discovery. The goal is to eliminate the mystery of the drug development process in order to emphasize the extensive, stringent and rigorous evaluations necessary to prove that a drug is safe and effective.

Drug development is divided into four main categories, with early steps setting the stage for later efforts:

1. Discovery and Development

2. Preclinical Research

3. Clinical Research

4. FDA Drug Review

Discovery

For any given disease or condition, researchers (in the private sector and government) look for new molecules and new technologies that might be useful in treating the targeted disease or condition. In this stage it is common to test thousands or tens of thousands of different compounds in the lab; only a small number will ever show any promise.

Development

Of the few compounds that show promise (for example, killing cancer cells in laboratory preparations), researchers then do further experiments moving from the lab to animals to humans to determine: how the new compound is taken up by the body and metabolized, potential benefits, best dosage, best way to give the drug (pill, shot), side effects, how different ethnic groups respond, how it interacts with other drugs, and how it compares to existing medications. The later stages of this process are accomplished through Preclinical and Clinical Research.

Preclinical Research

Before any potential drug can ever be given to a human, the drug has to undergo extensive in vitro testing (think mad scientist Petri dishes and glass vials) and then in vivo investigations. The latter are animal-based studies that look at pharmacokinetics (how a drug moves through a body — absorption, distribution, metabolism, and excretion) and pharmacodynamics (how the drug acts on the body — what the drug does to the body, the biochemical, physiological and molecular effects of the drug).

Clinical Research

Once a promising compound proves to be potentially safe and potentially effective against the target disease, we move to clinical research, which is divided into 4 main phases, each building on the previous:

Phase 1: determine human safety and dosage with 20–100 healthy volunteers; requires several months.

Phase 2: determine efficacy — does it work or not — and evaluate side effects, with up to several 100 people who suffer from the targeted disease; requires several months to 2 years.

Phase 3: confirm efficacy (or fail to) in larger number of participants and further evaluate possible adverse reactions in a larger test group, ranging from 300 to 3000 volunteers who suffer from the disease; requires 1 to 4 years. This is really where the rubber first hits the road, proving conclusively or not that the potential drug actually works and is safe to use. Because of the larger number of volunteers involved, more subtle problems and side effects can be discovered here that were not evident in the initial smaller trials. Many drugs fail at this critical point due to disappointing efficacy results or unexpected toxicity. Think about this failure point, well into development, the next time you look to some small, early, unregulated clinical trial as proof your magic elixir works. Think about this the next time you get excited about in vitro results before any human testing has been done on your miracle cure.

Phase 4: Once the FDA has approved the drug, mandatory clinical trials determine how the drug fares in the general population of disease sufferers in order to further understand issues of efficacy and safety; this requires several thousand volunteers. Sometimes this phase can reveal a subtle problem undetected in earlier trials or problem with some subset of the population that was not represented in large numbers previously.

FDA Drug Review

Except for the very early stages of discovery, the US Food and Drug Administration is involved in virtually all aspects of drug development outlined above. The different clinical research stages require prior FDA approval of an Investigational New Drug (IND) application. Once approved, and the developers satisfactorily complete all the different pre-clinical and clinical research phases, the FDA must then approve the New Drug Application (NDA) the purpose of which is to demonstrate that the drug is safe and effective for its intended use. This NDA must include everything up to and including Phase 3 clinical trial data. Before final approval, the developer must refine prescribing information (labeling) to ensure the drug label is accurate and properly describes the basis for approval and best use of the drug. Given the complexity of our biology, and the complexity of the drug development process, we commonly see “post approval” issues that may require additional studies.

Why Oversight Matters

When you take a drug, are you ever concerned that each pill might have a different dose, or might be contaminated in manufacturing, or might degrade on the shelf into something toxic? Are you concerned the drug is not safe if taken as directed? You are not, and you are not because of this rigorous process of approving new drugs.

When you take a remedy that you see on the internet, you have none of that assurance — you have no way, no possible way, of knowing if the drug is effective, safe, or free of contaminants or toxins. You have no way to know if taking the drug is safe or if the drug can damage organs or cause harm to your cardiovascular system. It matters not if a friend swears it works, or an entire community on the internet swears it works: without a rigorous review process you simply cannot know if it will cause harm or death. Without this review process you don’t even know if the promised ingredients are actually present — and in OTC supplements they are usually not, as we will see shortly.

Even if you take a drug approved for some other disease (say malaria), and you think you can use that drug (for example, hydroquinone) to treat something else (perhaps COVID-19), you risk life and limb. Since the drug is not approved for your new-found use you have no way to determine what dose to take, how frequently, or for how long. You cannot know if higher doses or longer exposure can lead to organ failure, heart failure or circulatory problems — because the drug was not tested for your off-label use.

There is no more reason to think an unapproved drug works off-label than any random choice of any random drug. If you are willing to accept an unproven cure, one that has not undergone a rigorous review process, you can adopt a simpler way to get something as good for whatever ails you: go to your local pharmacy, put on a blindfold, stumble down any aisle, randomly grab 5 bottles off the shelf, and you now have in your hand 5 drugs that are just as effective against the disease you are trying to cure. Your favorite unproven remedy is no better or worse than that.

From Bad Medicine to Good

We have learned the basic biology of viruses and revealed how viral nomenclature can helps us understand the origins of the pandemic. We endured a review of the drug development process to emphasize how rigorous testing and oversight are essential to ensure drug quality. We now highlight the real-world and documented risks of using unproven therapies that do not undergo such evaluation — like those touted on social media to cure or prevent COVID-19. That vignette about walking blind in a pharmacy is not theoretical. We in fact know from the world of supplements that lack of oversight and the absence of rigorous evaluation lead to the undesirable outcome of false claims.

People daily pop, drink and chow down on nutritional supplements with great abandon, without the slightest evidence that any of them have any potential benefit. But things are worse than that; not only is it not possible to know if the supplement has any health benefit, you actually do not know if the supplement contains the listed ingredients. You may well be taking something detrimental to health or something potentially healthy but in unsafe doses. This from an expose in the New York Times:

“Among the attorney general’s findings was a popular store brand of ginseng pills at Walgreens, promoted for “physical endurance and vitality,” that contained only powdered garlic and rice. At Walmart, the authorities found that its ginkgo biloba, a Chinese plant promoted as a memory enhancer, contained little more than powdered radish, houseplants and wheat — despite a claim on the label that the product was wheat- and gluten-free. Three out of six herbal products at Target — ginkgo biloba, St. John’s wort and valerian root, a sleep aid — tested negative for the herbs on their labels. But they did contain powdered rice, beans, peas and wild carrots. And at GNC, the agency said, it found pills with unlisted ingredients used as fillers, like powdered legumes, the class of plants that includes peanuts and soybeans, a hazard for people with allergies.”

Note that even if the supplements actually contained what was promised, the health claims (physical endurance, vitality, memory enhancement, sleep aid) are all just random claims with no supporting clinical evidence. Remember the random blind-folded walk down a pharmacy aisle.

The Times is not alone in their summary findings, as we see from an article from Consumer Health Choices:

“Supplement manufacturers routinely, and legally, sell their products without first having to demonstrate that they are safe and effective. Unlabeled ingredients found in many supplements are: bitter orange, chaparral, colloidal silver, coltsfoot, comfrey, country mallow, germanium, greater celandine, kava, lobelia, and yohimbe. The FDA has warned about at least eight of them, some as long ago as 1993. Of the more than 54,000 dietary supplement products in the Natural Medicines Comprehensive Database, more than 40,000 have no level of safety and effectiveness supported by scientific evidence.”

Next time you have an urge to take ginger or ginkgo biloba or St. John’s wort, just pop some frozen peas into your mouth; there is no evidence one is more healthful than the other.

The fact that many supplements do not even contain the labelled ingredients should be sufficient to cause some reflection on what would happen with prescription drugs if not tightly regulated. The fact that few supplement manufacturers offer predictability in their products or objective evidence for health claims of a particular supplement should raise eyebrows. Consider a cancer drug that did not actually contain the ingredients to treat that cancer, or which had variable doses with each pill. In contrast to most supplements, with prescription drugs any instances of mislabeling or mistakes in manufacturing could kill rather simply fail to cure a cold, or to build muscle mass, or to boost immunity.

Our real-world experience with the inherent unreliability of supplements should give us pause when accepting the unproven claims of a cure for any serious disease or condition. The untrustworthiness of unregulated supplements should make all of us deep skeptics of the unregulated and unproven cures circulating on the internet, or of testimony from a friend, or of the latest miracle claim plastered on grocery store magazines — or of the most recent assertions that hydroquinone is effective against COVID-19.

There is no room here to debunk the ocean of nonsense we encounter daily; this small sample of crazy with supplements is not even the tip of the tip of the iceberg. The insane claims surrounding probiotics and hormone supplements for example are worthy of a book each. But understand that unless you restrict your intake of drugs and supplements to those proven to be effective and safe through rigorous scientific evaluation, you are just randomly putting stuff in your mouth. A random walk down a pharmacy aisle.

The only way, the only way, to know if a supplement has valid medical purpose, or if the supplement contains the listed ingredients, or if a drug is safe and effective against a particular disease, is through the rigorous process of regulated drug development and manufacturing.

Yes, of course, evidence-based medicine (often conflated with western medicine) has its own set of serious problems and significant limitations. Clinical studies can be and have been tainted by pharmaceutical company sponsors or by doctors with financial interests in the outcome; negative data can be and has been buried or manipulated; drugs shown to be safe in small trials can turn out to have significant or even deadly side effects in a broader population; treatment with some drugs can lead to addiction; and interactions among different drugs can be hazardous. Biology is complex, and our understanding of disease incomplete, meaning that treatments are often developed by trial and error rather than based on first principles. But perhaps the biggest flaw with modern western medicine is that we have created a false expectation that our ills can be cured with a pill when in fact the cure more often lies in making difficult lifestyle changes. Smoking, lack of exercise and overeating come to mind.

But all of these flaws in modern medicine are amenable to improvement because the foundation is evidence-based. With scrutiny and reproducibility come accountability that eventually expose weaknesses to be addressed. Or at least that possibility exists, which is not the case for claims that are made with no attempt at rigorous evaluation at all. Unsubstantiated claims are immune to evaluation, which makes them inherently dangerous.

A healthy body is a finely tuned bundle of complex interacting feedback loops, each dependent on and impacting the other in an endless cycle of metabolism and catabolism. Taking a supplement or drug that has not been properly evaluated for its impact on this beautifully tuned biological marvel is not prudent.

So, let us avoid miracle cures, ignore conspiracy theories, and flatten the curve with responsible social behavior as we wait for a properly vetted vaccine to hit this virus where it hurts.