Coronavirus news & views

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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HIV And Coronaviruses: A Bad Combo

Africa is the continent least vaccinated for COVID-19 and it also has been where several CoV-2 variants have arisen: Beta in South Africa, most recently C.1.2 (not yet given a Greek letter designation) also from South Africa, and Eta in Nigeria. A possible reason for the appearance of these variants is because Africa is also home to the most immunocompromised people. HIV is common in Africa and tuberculosis is rampant on the continent.

One HIV-positive woman in South Africa was reported to carry active CoV-2 infection for 216 days, during which time it mutated 30 times according to Tulio de Oliveira, who runs gene-sequencing centers at two South African universities. This is concerning since South Africa has the world’s largest HIV epidemic. It is estimated to have 8.2 million people infected with HIV. While most of these take antiretroviral drugs, which keep the virus at bay, many do not. And neighboring countries, Botswana, Zimbabwe, and Eswatini also have very high HIV infection rates. The burden of HIV, TB and other chronic diseases is higher in these countries than in other countries around the world due to extreme poverty and poor health care for millions of Africans. When these people also become infected with CoV-2, they grow and shed the virus longer than someone with a good immune system and good health care. That means that the virus has longer to mutate in an infected, immunocompromised person.

In wealthier countries in the West, a rich debate is ongoing about whether to add another shot (booster) to already vaccinated people. One of the biggest arguments against this is that those booster vaccines are needed much more in poorer, and woefully under-vaccinated countries, such as those in Africa. The concern is that our boosters come at the expense of basic immunization of these impoverished countries, which facilitates the generation of troublesome viral variants. On the other hand, if CoV-2 is running rampant because the health care infrastructure in these countries is not up to delivering those vaccines, maybe it would be better making sure that richer countries are as protected as possible.

These are the proverbial two horns of a dilemma. Which horn would you choose?

Great News On The CoV-2 Vaccine Front

The news: Pharma giant, Pfizer, and its German biotech partner, BioNTech, just announced that preliminary indications show that its two-shot anti-CoV-2 vaccine is 90% effective in preventing infection. The study is not yet complete, meaning that this is based on what is called interim data analysis. All large scale clinical trials schedule such interim analysis in order to detect potential problems with the study such as potential side effects, enrollment problems, and to make a preliminary assessment on the trial's outcomes. The review is done by a Data and Safety Monitoring Board (DSMB), an independent panel of scientists and statisticians who are not part of the study. Using an independent DSMB allows study personnel to remain blinded as the trial proceeds.

In this case, the interim review of data by the DSMB compared the number of subjects in the placebo control group who became infected to the number of infected subjects who received both vaccine doses. This showed that vaccinated subjects were 90% less likely to be infected. The interim analysis also showed negligible adverse effects in the group who received the vaccine. While still preliminary, these results are encouraging. The study will continue over the next couple of months and even beyond in order to learn how long the immunity lasts and how effective it is in different populations including the elderly and other high risk groups. There seems to be a good chance that final approval will come around the end of year and vaccinations begin shortly after that.

Pfizer began manufacturing the vaccine a few months ago so that they would have a stockpile ready to distribute as soon as FDA approval comes. While this eliminates the usual post-approval delay to ramp up production capability, this strategy is a major gamble for the company since it is not guaranteed that the vaccine would be approved. If the vaccine does not pan out, the company will have to eat the cost for manufacturing a useless vaccine. On the other hand, if the vax is approved, Pfizer is poised to immediately deliver hundreds of millions of doses while their production efforts continue.

This is the first RNA vaccine tested in humans. The potential advantage of this approach is that it completely avoids using the virus itself. “Old fashioned,” vaccines required growing the virus in mass quantities and then crippling or killing it for injection, which is labor intensive, entails certain risks, and is expensive. Instead, the Pfizer vaccine involves cloning part of the genome that is thought to be a target for the immune system, packaging it in an inert lipid nanoparticle, and injecting it in order to aggravate the immune system. The idea is that this fragment of the viral genome will be taken up by human cells and the cellular machinery will use it to produce the viral protein that can stimulate an immune response in the absence of the virus itself. The cells will soon degrade the cloned RNA fragment leaving only immunological memory with which to fight reinfection.

What is next? While this is encouraging news, this brings us to perhaps a larger problem to solve, which is how the early vaccine will be most effectively and fairly distributed. By the end of the year, Pfizer will have a few hundred million doses and predicts it can produce 1.3 billion doses in 2021. Since this is a two-dose vaccine, that means that that will be enough to vaccinate about 650 million people, or less than 10% of the 7.8 billion who live in the world. Who will have priority for the first doses of the vaccine? Will front line health care workers and high risk people be given the first doses? What about world-wide distribution? Since the vaccine is being tested and made by an American company (Pfizer) using technology developed by a German biotech (BioNTech), should those two countries reap the immediate benefit of the early limited doses of vaccine, while the rest of the world waits months for sufficient doses of the vax to meet their needs?

The WHO recommends that the vax be distributed to each country based on its population. Another recommendation from the National Academies of Sciences, Engineering, and Medicine is to distribute it based on each country's number of health care workers and high risk populations. Others argue that the US should base distribution on racial and socioeconomic disparities. U Penn doctor and medical ethicist, Ezekiel Emanuel (a primary author of Obamacare), proposed a Fair Priority Model that would favor countries with younger populations, weaker economies, and with poor health access--in other words, third world countries.

These suggestions seem moot since advanced purchase agreements already give 80% of that early vax supply to the US, UK, Canada, and Japan.

Another issue regarding distribution is that the vaccine needs to be stored and transported in ultra-cold conditions (-80 degree C. or -112 degrees F.). Such ultra-cold storage facilities are in short supply around the world, meaning that countries with poor health infrastructure will be at a significant disadvantage because they cannot store the vaccine. This ultra-cold storage requirement will also make it challenging for the vax to be administered in a normal doctor’s office or pharmacy, which typically do not have ultra-cold freezers. 

Logistics: Once the vaccine is approved, the enormous task of getting billions of doses distributed across the US and around the world begins. This is where Trump’s Operation Warp Speed comes into to play. Even though the Pfizer vaccine was not developed under that program, the logistics of its distribution will be part of Warp Speed, which also includes massive pre-planning for storing, distributing, and delivering two doses of the vaccine ultimately to 300 million Americans. The US Army Materiel Command, headed by four star general Gus Perna, has been tapped for this undertaking. He is the one who sees that American military forces around the globe have sufficient housing, clothing, food, and beer. So, he seems like a good choice to oversee the distribution of billions of doses of a vaccine. You can see more about this on the Nov 8 episode of 60 Minutes. The logistics and planning for this almost makes the development of the new vaccine a trivial issue.

There is joke that goes something like this: Hell is where the English are the cooks, Italians the managers, and Americans the soccer lovers. Heaven is where the English are the soccer lovers, Italians the cooks and Americans the managers. This is a good example of American large-scale management, so we must be in heaven.

Refusing To Treat COVID Patients Based On “Quality Of Life” Determinations

FYI: While your humble blogger earned a PhD in viral immunology from the University of Texas, and spent most of his career investigating the causes and cures of leukemia at UCLA and the University of Wisconsin, he also was trained in ethics at Indiana University, the University of Montana, and Calvin College. He taught bioethics and research ethics at the U of W. His closet hooks are full of different hats.

Biomedicine is rife with ethical conundrums, a few of which already have been mentioned in these pages about the coronavirus pandemic, to wit: Should we wave inspection of vaccine manufacturing facilities and risk production mistakes in order to speed release of a CoV-2 vaccine, which will save lives? Or, whose rights do we ignore during a pandemic—the freedom to live as we choose vs the freedom to remain free of infection? Or, do we abandon all social restrictions in attempt to achieve herd immunity via natural infection, realizing that we would be sacrificing many to the disease? All, conundrums, indeed.

Ethical dilemmas entail at least two conflicting choices, neither of which is perfectly good nor perfectly bad. That is why these problems are often referred to as “horns of a dilemma.” Which horn should we embrace, and which should we avoid, knowing that both can stick us?

An ethical dilemma has arisen in healthcare circles, but for which the popular press has largely been silent. This issue is about how “quality of life” factors into health care decisions for COVID-19 patients. The following example of how this ethical conundrum can play out is excerpted and modified from the journal, First Things.

A man, Michael, was refused treatment for COVID-19 because the hospital he was admitted to and State bureaucrats believed that he did not enjoy sufficient quality of life to warrant curative treatment for the disease. In 2017, Michael had a heart attack that caused brain damage leaving him a quadriplegic and suffering frequent seizures. But he was conscious, able to do simple math calculations, answer trivia questions, and interact with his family. Then, in late Spring of 2020, he caught COVID-19 and was hospitalized. The hospital decided to withhold his tube feeding despite the objections of his wife, and the fact that he had a fair chance of surviving if provided with appropriate COVID treatment and sustenance care. He died on June 11.

He was denied care because his doctors determined that he did not have a sufficient “quality of life” to justify treatment. Because of his disabilities, saving his life was deemed “futile.” The medical team and the “State,” through a court appointed guardian, reasoned that treatment for COVID-19 would not improve the quality of his life (meaning, he would remain quadriplegic and cognitively disabled if he survived the disease); therefore, they decided to end all treatment care except hospice comfort care.

His wife, Melissa, had been appointed Michael’s temporary guardian, but she was in a legal struggle with Michael’s sister over his custody, a dispute that predated Michael’s hospitalization. Family Eldercare, a nonprofit agency, was then appointed interim guardian until a final decision could be made about permanent guardianship. Hospital doctors convinced Family Eldercare to approve Michael’s transfer to hospice care where he would only receive palliative care and not curative or sustenance care. Michael died of pneumonia after six days on hospice; the withdrawal of nutrition and hydration having no doubt weakened his body’s ability to fight disease. Even without pneumonia, Michael would have soon died of dehydration.

Melissa recorded her conversation with an unnamed physician and posted it on YouTube so we can all hear for ourselves.  Here’s the substance of the conversation from the YouTube transcript, with my commentary.

Doctor: At this point, the decision is, do we want to be extremely aggressive with his care or do we feel like this will be futile? And the big question of futility is one that we always question. The issue is: Will this help him improve the quality of life, will this help him improve anything, will it ultimately change the outcome? And the thought is the answer is no to all of those.

Melissa: What would make you say no to all of those?

Doctor: As of right now the quality of life, he doesn’t have much of one.

Melissa: What do you mean? Because he was paralyzed with a brain injury, he doesn’t have a quality of life?

Doctor: Correct

My Comment: The doctor did not base his decision about Michal’s medical care on the illness for which he was hospitalized, but on his unrelated disability. This is a classic example of applying the invidious “quality of life” ethic, which deems people with disabilities, the elderly, the chronically ill, and the dying to have a lower worth than the healthy, able-bodied, and young. Back to the conversation…

Melissa: Who gets to make that decision whether somebody’s quality of life, if they have a disability that their quality of life is not good?

Doctor: Well, it’s definitely not me. I don’t make that decision. However, will it affect his quality, will it improve his quality of life, and the answer is no.

My Comment: After denying that he had any part in determining Michael’s quality of life, the Doctor then admits that he believes that Michael’s quality of life is negligible. By doing so, he is being duplicitous regarding his role in the decision, and he is not acting as Michael’s doctor, beholden to the Hippocratic Oath he took. Rather, he is acting as an agent for the hospital and State bureaucracies rather than acting in Michael’s interest, a dramatic violation of the Oath he took. Back to the conversation…

Melissa: Why wouldn’t it? Being able to live isn’t improving the quality of life?

Doctor: There’s no improvement with being intubated, with a bunch of lines and tubes in your body and being on a ventilator for more than two weeks. Each of our people here have COVID and they are in respiratory failure. They’ve been here for more than two weeks.

Comment: The Doctor again makes a statement of his opinion of Michael’s quality of life. He admits that many of their OOVID patients are in respiratory failure and on ventilators, but implies that they are more valuable than Michael and deserve such therapy, while Michael does not.

 Melissa: So the fact that you are killing someone doesn’t make sense in your mind?

Doctor: We don’t think it’s killing. Because I don’t know when or not if he will die. But at this point I don’t think it would be humane or compassionate to put a breathing tube in this man and do the lines and the tubes and all that stuff because I don’t think it will benefit him.

Melissa: And I totally agree with you on the intubation part of it. I don’t want him intubated. But I also don’t think you should just sit him somewhere to be comfortable until he finally just drifts away. That to me is futile too. That’s saying you’re not trying to save someone’s life. You’re just watching them go. The ship is sailing. I mean that just doesn’t make any sense to me to not try. I don’t get that part. I don’t like that part.

Doctor: But what I’m going to tell you is that this is the decision between the medical community and the State.

Melissa: And the State. Forget about his wife and his family and his five kids.

Doctor: I have nothing to do with that.

The recording ends there. 

At first blush, it might seem like a reasonable decision to withhold essential care from someone as damaged as Michael was, but what if we change the selection criteria from “quality of life” to “preciousness of life?” Wasn’t his life as precious as everybody else’s, especially to his family? It was not, according to Michael's doctors and faceless bureaucrats in his State who had never met him, all of whom believed that they could better judge Michael’s worth better than his family could. And, what about Michael’s wishes? The article did not indicate whether, after his hospitalization, he was able to express his desires in the matter, but I will assume he was incapable of doing so. In which case, the medical ethicist must look at Michael’s family as well as his life near the time he was hospitalized. Before catching COVID-19, were his actions consistent with someone who wanted to live, even with his disabilities? Even if a hospitalized patient cannot communicate, it is still possible to divine his wishes from the period before he became, possibly temporarily, non-communicative due to the disease. That divination is more relevant than faceless bureaucrats when making life and death decisions for him.

This is the great ethical problem of quality of life decisions being made by impersonal, anonymous administrators who can overrule the wishes of a patient’s immediate family and even the demonstrated wishes of the patient. The bottom line is to make sure you have your final wishes legally documented and use power of attorney to put your fate in the hands of highly trusted family or friends.

Even then, you still might encounter faceless bureaucrats making life and death decisions for you based on how they judge the quality of your life.

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