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FTR #1121 This program was recorded in one, 60-minute segment.
Introduction: OyaGen, Inc. has used a drug developed, tested and FDA-approved that successfully treats and–apparently–cures Covid-19. Interestingly and, perhaps, significantly, the trials were conducted at Fort Detrick. As seen in FTR #‘s 1119 and 1120, the military has been heavily involved in researching viruses of this type.
There continues to be enormous emphasis on Gilead Sciences by hedge funds including Renaissance Technologies. Robert Mercer stepped down as CEO of the firm at the end of 2017, as publicity around Cambridge Analytica and the fallout from the Charlottesville march made him something of a PR liability. Usually in such situations, people like Mercer remain as key investors.
In FTR #1118, we noted that the Board of Directors of the firm is “interesting.” The “disappointing” performance of Gilead Sciences changed dramatically with the Covid-19 outbreak. ” . . . . Until Monday, when it fell in a brutal market rout, Gilead’s stock price had defied the overall market decline of recent weeks, rising almost 20 percent from Feb. 21 to March 6, on hopes that the drug could provide the first treatment for covid-19. The lack of treatment helps explain why. The stock price increased 5 percent on Feb. 24 alone when a top official of the World Health Organization pinned much of the world’s hopes for a treatment on the drug. . . .”
Again, in FTR #‘s 1119 and 1120 we looked at the profound involvement of the Pentagon in researching coronaviruses like Covid-19, as well as DARPA’s deep involvement with companies approved to begin working on vaccines. Now, Medicago, another DARPA-funded company, claims to have a vaccine ready for trial. “. . . . Using plants and genetically engineered agrobacteria works faster than eggs also makes the vaccine much easier to produce at scale, which, in part, is why the U.S. military has invested in the company. In 2010, the Defense Advanced Research Projects Agency, or DARPA, put together a $100 million program dubbed Blue Angel to look into new forms of vaccine discovery and production. A big chunk of that money went to Medicago to build a facility in North Carolina, where they showed that they could find a vaccine in just 20 days, then rapidly scale up production. . . .”
Next, we turn to an article noting that the characteristics of the COVID-19 disease has remarkable overlap with a hypothetical disease, dubbed “Disease X.” In 2018, the World Health Organization emphasized an alarming characteristic of “hypothetical” “Disease X” that appears to be shared with SARS-CoV‑2: the ability to rapidly morph from a mild to deadly disease. The sudden turn towards a deadly disease appears to be due, in part, to an overly aggressive immune response that ends up ravaging the lungs. As one expert points out, this is the same pattern seen in the 1918 “Spanish flu” pandemic.
In FTR #1117, we reviewed the fact that military researchers had successfully recovered DNA from that infamous 1918 flu virus. as will be seen below, that virus was re-created in a laboratory in 2005.
So the WHO warned a couple years ago about a hypothetical “Disease X” disease that was highly contagious with the ability to spread with asymptomatically, is mild in most cases but with the ability to suddenly turn deadly. And here we are two years later with a disease that fits that profile. It was a pretty prescient prediction.
Note, also, that Marion Koopmans–head of viroscience at Erasmus Medical Center in Rotterdam and one of the WHO personnel who opined that Covid-19 was “Disease X” worked at the same institution as the researchers who performed gain-of-function experiments on the HN51 Avian Bird Flu virus, adapting to ferrets and making it communicable through casual respiratory activity. Those GOF experiements were also discussed in FTR #1117.
” . . . . From recent reports about the stealthy ways the so-called Covid-19 virus spreads and maims, a picture is emerging of an enigmatic pathogen whose effects are mainly mild, but which occasionally — and unpredictably — turns deadly in the second week. . . . The doctor [Li Wenliang], who was in good health prior to his infection, appeared to have a relatively mild case until his lungs became inflamed, leading to the man’s death two days later, said Linfa Wang, who heads the emerging infectious disease program at Duke-National University of Singapore Medical School. A similar pattern of inflammation noted among Covid-19 patients was observed in those who succumbed to the 1918 ‘Spanish flu’ pandemic . . .”
We wonder if variants of the Covid-19 may have been modified to infect the upper respiratory tract and/or modified with DNA from the resurrected 1918 “Spanish Flu”?
Peter Daszak of the WHO once again, voiced the (self-fulfilling?) opinion/prophecy that Covid-19 is indeed “Disease X.”
A key factor spurring our suspicion concerning genetic-engineering of one or more variant of the Covid-19 virus concerns a 2015 Gain-of-Function experiment: “Ralph Baric, an infectious-disease researcher at the University of North Carolina at Chapel Hill, last week (November 9) published a study on his team’s efforts to engineer a virus with the surface protein of the SHC014 coronavirus, found in horseshoe bats in China, and the backbone of one that causes human-like severe acute respiratory syndrome (SARS) in mice. The hybrid virus could infect human airway cells and caused disease in mice. . . . The results demonstrate the ability of the SHC014 surface protein to bind and infect human cells, validating concerns that this virus—or other coronaviruses found in bat species—may be capable of making the leap to people without first evolving in an intermediate host, Nature reported. They also reignite a debate about whether that information justifies the risk of such work, known as gain-of-function research. ‘If the [new] virus escaped, nobody could predict the trajectory,’ Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris, told Nature. . . .”
The above-mentioned Ralph Baric–who did the gain-of-function modification on the Horseshoe Bat coronavirus, has been selected to engineer the Covid-19.
Note what might be termed a “virologic Jurassic Park” manifestation: ” . . . . . . . . The technology immediately created bio-weapon worries. . . . Researchers at the US Centers for Disease Control and Prevention (CDC) drove that point home in 2005 when they resurrected the influenza virus that killed tens of millions in 1918–1919. . . .”
1a. OyaGen, Inc. has used a drug developed, tested and FDA-approved that successfully treats and–apparently–cures Covid-19. Interestingly and, perhaps, significantly, the trials were conducted at Fort Detrick. As seen in FTR #‘s 1119 and 1120, the military has been heavily involved in researching viruses of this type.
A vaccine for COVID-19 is likely years away. Yet a drug tested in a lab three weeks ago has been found to stop the virus from spreading from cell to cell.
The stunning announcement comes from a Rochester biotech company called OyaGen, Inc. The company is seeking to fast-track the formula to treat people who become infected.
“A treatment right now is the priority,” said Dr. Harold Smith of OyaGen. He added the drug already has FDA approval for another use.
The tests were conducted at the federal government’s integrated research facility in Fort Detrick, Md. A drug called Oya 1 had already been proven in lab tests there to be effective against Ebola.
“If it worked for Ebola, is it absolutely unique to Ebola, or would it work on other viruses?” asked Dr. Smith – though he said an actual drug for human consumption was never pursued.
The coronavirus was still new and contained to Wuhan, China when a sample of the live virus was shipped to the government lab for testing with Oya 1. Test samples viewed under a microscope show a clear “before” and “after” that indicates properties that allowed the virus to grow and spread were neutralized.
“The drug was so effective that, even though we got through our dose-testing, we had literally sterilized the culture of the virus, so we knew this was a powerful thing,” said Dr. Smith.
Under a different name, Oya‑1 was first developed in the 1960s as a treatment for cancer. It was later shelved as ineffective, but not before it received approval from the Food and Drug Administration. Safe dosage levels were determined for men, women and children.
“Clinical trials have already been done on this compound and, if safety is a main issue, we feel safety has been addressed years ago,” said Dr. Smith.
He said preliminary research indicates a single dose of the medicine stops the progression of COVID-19 for eight days and continues to work at half-strength for another four days.
The question is whether the drug will react to the virus the same way in the body as it has in the lab. When an approved drug is proposed for a new use, the FDA usually requires new clinical trials.
…
OyaGen says the live virus tests were conducted and validated by a third party – the U‑S government, and argue that is also a reason the drug should be fast-tracked.
“You’ve got this compound that’s absolutely lethal to the virus, and we know it has a margin of safety in people,” said Dr. Smith. “What are we waiting for?”
1b. There continues to be enormous emphasis on Gilead Sciences by hedge funds including Renaissance Technologies. Robert Mercer stepped down as CEO of the firm at the end of 2017, as publicity around Cambridge Analytica and the fallout from the Charlottesville march made him something of a PR liability. Usually in such situations, people like Mercer remain as key investors.
In FTR #1118, we noted that the Board of Directors of the firm is “interesting.”
It has been a fantastic year for equity investors as Donald Trump pressured Federal Reserve to reduce interest rates and finalized the first leg of a trade deal with China. If you were a passive index fund investor, you had seen gains of 31% in your equity portfolio in 2019. However, if you were an active investor putting your money into hedge funds’ favorite stocks, you had seen gains of more than 41%. In this article we are going to take a look at how hedge funds feel about a stock like Gilead Sciences, Inc. (NASDAQ:GILD) and compare its performance against hedge funds’ favorite stocks.
Gilead Sciences, Inc. (NASDAQ:GILD) was in 58 hedge funds’ portfolios at the end of the third quarter of 2019. GILD has seen an increase in hedge fund interest recently. . . .
. . . . The largest stake in Gilead Sciences, Inc. (NASDAQ:GILD) was held by Renaissance Technologies, which reported holding $933.9 million worth of stock at the end of September. It was followed by D E Shaw with a $349.9 million position. . . . Other investors bullish on the company included Two Sigma Advisors, AQR Capital Management, and GLG Partners. In terms of the portfolio weights assigned to each position Copernicus Capital Management allocated the biggest weight to Gilead Sciences, Inc. (NASDAQ:GILD), around 11.67% of its 13F portfolio. Healthcare Value Capital is also relatively very bullish on the stock, earmarking 8.01 percent of its 13F equity portfolio to GILD.
. . . . Our calculations showed that top 20 most popular stocks among hedge funds returned 41.1% in 2019 through December 23rd and outperformed the S&P 500 ETF (SPY) by 10.1 percentage points. Unfortunately GILD wasn’t nearly as popular as these 20 stocks and hedge funds that were betting on GILD were disappointed as the stock returned 10.8% so far in 2019 (through 12/23) and trailed the market. . . . .
1c. The “disappointing” performance of Gilead Sciences changed dramatically with the Covid-19 outbreak. ” . . . . Until Monday, when it fell in a brutal market rout, Gilead’s stock price had defied the overall market decline of recent weeks, rising almost 20 percent from Feb. 21 to March 6, on hopes that the drug could provide the first treatment for covid-19. The lack of treatment helps explain why. The stock price increased 5 percent on Feb. 24 alone when a top official of the World Health Organization pinned much of the world’s hopes for a treatment on the drug. . . .”
. . . . Now the drug, [remdesivir] created by pharmaceutical giant Gilead Sciences, is being tested in new clinical trials, and global health authorities deem it the most promising of possible treatments for people who are severely ill with the novel coronavirus, which causes the covid-19 disease. Because it is a “broad spectrum’’ drug that has been effective against multiple viral targets in the lab and in animals, the strategy could work, experts said. . . .
Gilead, the National Institutes of Health and Chinese health authorities are racing to test it on hundreds of people in controlled clinical trials, including a patient who was quarantined in Nebraska after being removed from the Diamond Princess cruise ship. Axios reported this month that Gilead acted so quickly that it did not even wait for required approval by the Food and Drug Administration before it shipped doses to China. Asked to respond, Gilead said it thinks its “limited shipments’’ were made in compliance with U.S. law.
. . . . Until Monday, when it fell in a brutal market rout, Gilead’s stock price had defied the overall market decline of recent weeks, rising almost 20 percent from Feb. 21 to March 6, on hopes that the drug could provide the first treatment for covid-19.
The lack of treatment helps explain why. The stock price increased 5 percent on Feb. 24 alone when a top official of the World Health Organization pinned much of the world’s hopes for a treatment on the drug.
“There is only one drug right now that we think may have real efficacy, and that’s remdesivir,” said Bruce Aylward, WHO’s assistant director general. Ten days later, RBC Capital Markets gave it only a 50 percent chance of succeeding as a treatment.
The mixed signals have done little to dampen interest. There have been desperate pleas for supplies to treat patients on a ‘compassionate use’ basis.
. . . . But drug companies also have been accused of not pursuing vaccines and antiviral treatments aggressively because the commercial markets for such drugs are weak. . . .
. . . . Given the large degree of public financial support, debates are already flaring about how much Gilead should charge for its treatment if it ever makes it to market.
Congress and President Trump authorized up to $3 billion last week for efforts by academic researchers and drug companies to develop vaccines and treatments for coronavirus, part of an $8.3 billion emergency spending bill. The industry successfully opposed efforts by some House Democrats to attach guarantees for affordable prices for vaccines or treatments that result. . . .”
1d. Again, in FTR #‘s 1119 and 1120 we looked at the profound involvement of the Pentagon in researching coronaviruses like Covid-19, as well as DARPA’s deep involvement with companies approved to begin working on vaccines. Now, Medicago, another DARPA-funded company, claims to have a vaccine ready for trial. “. . . . Using plants and genetically engineered agrobacteria works faster than eggs also makes the vaccine much easier to produce at scale, which, in part, is why the U.S. military has invested in the company. In 2010, the Defense Advanced Research Projects Agency, or DARPA, put together a $100 million program dubbed Blue Angel to look into new forms of vaccine discovery and production. A big chunk of that money went to Medicago to build a facility in North Carolina, where they showed that they could find a vaccine in just 20 days, then rapidly scale up production. . . .”
A Canadian company says that it has produced a COVID-19 vaccine just 20 days after receiving the coronavirus’s genetic sequence, using a unique technology that they soon hope to submit for FDA approval.
Medicago CEO Bruce Clark said his company could produce as many as 10 million doses a month. If regulatory hurdles can be cleared, he said in a Thursday interview, the vaccine could start to become available in November 2021. . . .. . . . Using plants and genetically engineered agrobacteria works faster than eggs also makes the vaccine much easier to produce at scale, which, in part, is why the U.S. military has invested in the company.
In 2010, the Defense Advanced Research Projects Agency, or DARPA, put together a $100 million program dubbed Blue Angel to look into new forms of vaccine discovery and production. A big chunk of that money went to Medicago to build a facility in North Carolina, where they showed that they could find a vaccine in just 20 days, then rapidly scale up production. . . .
1d. Next, we turn to an article noting that the characteristics of the COVID-19 disease has remarkable overlap with a hypothetical disease, dubbed “Disease X.” In 2018, the World Health Organization emphasized an alarming characteristic of “hypothetical” “Disease X” that appears to be shared with SARS-CoV‑2: the ability to rapidly morph from a mild to deadly disease. The sudden turn towards a deadly disease appears to be due, in part, to an overly aggressive immune response that ends up ravaging the lungs. As one expert points out, this is the same pattern seen in the 1918 “Spanish flu” pandemic.
In FTR #1117, we reviewed the fact that military researchers had successfully recovered DNA from that infamous 1918 flu virus. as will be seen below, that virus was re-created in a laboratory in 2005.
So the WHO warned a couple years ago about a hypothetical “Disease X” disease that was highly contagious with the ability to spread with asymptomatically, is mild in most cases but with the ability to suddenly turn deadly. And here we are two years later with a disease that fits that profile. It was a pretty prescient prediction.
Note, also, that Marion Koopmans–head of viroscience at Erasmus Medical Center in Rotterdam and one of the WHO personnel who opined that Covid-19 was “Disease X” worked at the same institution as the researchers who performed gain-of-function experiments on the HN51 Avian Bird Flu virus, adapting to ferrets and making it communicable through casual respiratory activity. Those GOF experiements were also discussed in FTR #1117.
” . . . . From recent reports about the stealthy ways the so-called Covid-19 virus spreads and maims, a picture is emerging of an enigmatic pathogen whose effects are mainly mild, but which occasionally — and unpredictably — turns deadly in the second week. . . . The doctor [Li Wenliang], who was in good health prior to his infection, appeared to have a relatively mild case until his lungs became inflamed, leading to the man’s death two days later, said Linfa Wang, who heads the emerging infectious disease program at Duke-National University of Singapore Medical School. A similar pattern of inflammation noted among Covid-19 patients was observed in those who succumbed to the 1918 ‘Spanish flu’ pandemic . . .”
We wonder if variants of the Covid-19 may have been modified to infect the upper respiratory tract and/or modified with DNA from the resurrected 1918 “Spanish Flu”?
“Coronavirus May Be ‘Disease X’ Health Experts Warned About” By Jason Gale; Bloomberg; 02/22/2020
* Picture is emerging of an unpredictable, enigmatic pathogen
* SARS-like lung inflammation seen in severe Covid-19 casesThe World Health Organization cautioned years ago that a mysterious “disease X” could spark an international contagion. The new coronavirus illness, with its ability to quickly morph from mild to deadly, is emerging as a contender.
From recent reports about the stealthy ways the so-called Covid-19 virus spreads and maims, a picture is emerging of an enigmatic pathogen whose effects are mainly mild, but which occasionally — and unpredictably — turns deadly in the second week. In less than three months, it’s infected almost 78,000 people, mostly in China, and killed more than 2,300. Emerging hot spots in South Korea, Iran and Italy have stoked further alarm.
“Whether it will be contained or not, this outbreak is rapidly becoming the first true pandemic challenge that fits the disease X category,” Marion Koopmans, head of viroscience at Erasmus University Medical Center in Rotterdam, and a member of the WHO’s emergency committee, wrote Wednesday in the journal Cell.
The disease has now spread to more than two dozen countries and territories. Some of those infected caught the virus in their local community and have no known link to China, the U.S. Centers for Disease Control and Prevention said.
“We are not seeing community spread here in the United States yet, but it’s very possible — even likely — that it may eventually happen,” Nancy Messonnier, director of the CDC’s National Center for Immunization and Respiratory Diseases, told reporters Friday.
Unlike SARS, its viral cousin, the Covid-19 virus replicates at high concentrations in the nose and throat akin to the common cold, and appears capable of spreading from those who show no, or mild, symptoms. That makes it impossible to control using the fever-checking measures that helped stop SARS 17 years ago.
Spreading Surreptitiously
A cluster of cases within a family living in the Chinese city of Anyang is presumed to have begun when a 20-year-old woman carried the virus from Wuhan, the outbreak’s epicenter, on Jan. 10 and spread it while experiencing no illness, researchers said Friday in the Journal of the American Medical Association.
Five relatives subsequently developed fever and respiratory symptoms. Covid-19 is less deadly than SARS, which had a case fatality rate of 9.5%, but appears more contagious. Both viruses attack the respiratory and gastrointestinal tracts, via which they can potentially spread.
While more than 80% of patients are reported to have a mild version of the disease and will recover, about one in seven develops pneumonia, difficulty breathing and other severe symptoms. About 5% of patients have critical illness, including respiratory failure, septic shock and multi-organ failure.
“Unlike SARS, Covid-19 infection has a broader spectrum of severity ranging from asymptomatic to mildly symptomatic to severe illness that requires mechanical ventilation,” doctors in Singapore said in a paper in the same medical journal Thursday. “Clinical progression of the illness appears similar to SARS: patients developed pneumonia around the end of the first week to the beginning of the second week of illness.”
Unpredictable Illness
Older adults, especially those with chronic conditions, such as hypertension and diabetes, have been found to have a higher risk of severe illness. Still, “the experience to date in Singapore is that patients without significant co-morbid conditions can also develop severe illness,” they said.
Li Wenliang, the 34-year-old ophthalmologist who was one of the first to warn about the coronavirus in Wuhan, died earlier this month after receiving antibodies, antivirals, antibiotics, oxygen and having his blood pumped through an artificial lung.
Update: Li Wenliang is currently in critical condition. His heart reportedly stopped beating at around 21:30. He was then given treatment with ECMO(extra-corporeal membrane oxygenation). https://t.co/ljhMSwHBXB
— Global Times (@globaltimesnews) February 6, 2020The doctor, who was in good health prior to his infection, appeared to have a relatively mild case until his lungs became inflamed, leading to the man’s death two days later, said Linfa Wang, who heads the emerging infectious disease program at Duke-National University of Singapore Medical School.
A similar pattern of inflammation noted among Covid-19 patients was observed in those who succumbed to the 1918 “Spanish flu” pandemic, said Gregory A. Poland, the Mary Lowell Leary emeritus professor of medicine, infectious diseases, and molecular pharmacology and experimental therapeutics at the Mayo Clinic in Rochester, Minnesota.
“Whenever, you have an infection, you have a battle going on,” Poland said in a phone interview Thursday. “And that battle is a battle between the damage that the virus is doing, and the damage the body can do when it tries to fight it off.” . . . .
2. Peter Daszak of the WHO once again, voiced the (self-fulfilling?) opinion/prophecy that Covid-19 is indeed “Disease X.”
“We Knew Disease X Was Coming. It’s Here Now.” by Peter Daszak; The New York Times; 02/27/2020
In early 2018, during a meeting at the World Health Organization in Geneva, a group of experts I belong to (the R&D Blueprint) coined the term “Disease X”: We were referring to the next pandemic, which would be caused by an unknown, novel pathogen that hadn’t yet entered the human population. As the world stands today on the edge of the pandemic precipice, it’s worth taking a moment to consider whether Covid-19 is the disease our group was warning about.
Disease X, we said back then, would likely result from a virus originating in animals and would emerge somewhere on the planet where economic development drives people and wildlife together. Disease X would probably be confused with other diseases early in the outbreak and would spread quickly and silently; exploiting networks of human travel and trade, it would reach multiple countries and thwart containment. Disease X would have a mortality rate higher than a seasonal flu but would spread as easily as the flu. It would shake financial markets even before it achieved pandemic status.
In a nutshell, Covid-19 is Disease X. . . .
3. A key factor spurring our suspicion concerning genetic-engineering of one or more variant of the Covid-19 virus concerns a 2015 Gain-of-Function experiment: “Ralph Baric, an infectious-disease researcher at the University of North Carolina at Chapel Hill, last week (November 9) published a study on his team’s efforts to engineer a virus with the surface protein of the SHC014 coronavirus, found in horseshoe bats in China, and the backbone of one that causes human-like severe acute respiratory syndrome (SARS) in mice. The hybrid virus could infect human airway cells and caused disease in mice. . . . The results demonstrate the ability of the SHC014 surface protein to bind and infect human cells, validating concerns that this virus—or other coronaviruses found in bat species—may be capable of making the leap to people without first evolving in an intermediate host, Nature reported. They also reignite a debate about whether that information justifies the risk of such work, known as gain-of-function research. ‘If the [new] virus escaped, nobody could predict the trajectory,’ Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris, told Nature. . . .”
“Lab-Made Coronavirus Triggers Debate” by Jef Akst; The Scientist; 11/16/2015
Ralph Baric, an infectious-disease researcher at the University of North Carolina at Chapel Hill, last week (November 9) published a study on his team’s efforts to engineer a virus with the surface protein of the SHC014 coronavirus, found in horseshoe bats in China, and the backbone of one that causes human-like severe acute respiratory syndrome (SARS) in mice. The hybrid virus could infect human airway cells and caused disease in mice, according to the team’s results, which were published in Nature Medicine.
The results demonstrate the ability of the SHC014 surface protein to bind and infect human cells, validating concerns that this virus—or other coronaviruses found in bat species—may be capable of making the leap to people without first evolving in an intermediate host, Nature reported. They also reignite a debate about whether that information justifies the risk of such work, known as gain-of-function research. “If the [new] virus escaped, nobody could predict the trajectory,” Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris, told Nature.
In October 2013, the US government put a stop to all federal funding for gain-of-function studies, with particular concern rising about influenza, SARS, and Middle East respiratory syndrome (MERS). “NIH [National Institutes of Health] has funded such studies because they help define the fundamental nature of human-pathogen interactions, enable the assessment of the pandemic potential of emerging infectious agents, and inform public health and preparedness efforts,” NIH Director Francis Collins said in a statement at the time. “These studies, however, also entail biosafety and biosecurity risks, which need to be understood better.”
Baric’s study on the SHC014-chimeric coronavirus began before the moratorium was announced, and the NIH allowed it to proceed during a review process, which eventually led to the conclusion that the work did not fall under the new restrictions, Baric told Nature. But some researchers, like Wain-Hobson, disagree with that decision.
The debate comes down to how informative the results are. “The only impact of this work is the creation, in a lab, of a new, non-natural risk,” Richard Ebright, a molecular biologist and biodefence expert at Rutgers University, told Nature.
But Baric and others argued the study’s importance. “[The results] move this virus from a candidate emerging pathogen to a clear and present danger,” Peter Daszak, president of the EcoHealth Alliance, which samples viruses from animals and people in emerging-diseases hotspots across the globe, told Nature.
4. The above-mentioned Ralph Baric–who did the gain-of-function modification on the Horseshoe Bat coronavirus, has been selected to engineer the Covid-19.
Note what might be termed a “virologic Jurassic Park” manifestation: ” . . . . The technology immediately created bio-weapon worries. . . . Researchers at the US Centers for Disease Control and Prevention (CDC) drove that point home in 2005 when they resurrected the influenza virus that killed tens of millions in 1918–1919. . . .”
The world is watching with alarm as China struggles to contain a dangerous new virus, now being called SARS-CoV‑2. It has quarantined entire cities, and the US has put a blanket ban on travellers who’ve been there. Health officials are scrambling to understand how the virus is transmitted and how to treat patients.
But in one University of North Carolina lab, there’s a different race. Researchers are trying to create a copy of the virus. From scratch.
Led by Ralph Baric, an expert in coronaviruses—which get their name from the crown-shaped spike they use to enter human cells—the North Carolina team expects to recreate the virus starting only from computer readouts of its genetic sequence posted online by Chinese labs last month.
The remarkable ability to “boot up” viruses from genetic instructions is made possible by companies that manufacture custom DNA molecules, such as Integrated DNA Technology, Twist Bioscience, and Atum. By ordering the right genes, which cost a few thousand dollars, and then stitching them together to create a copy of the coronavirus genome, it’s possible to inject the genetic material into cells and jump-start the virus to life.
The ability to make a lethal virus from mail-order DNA was first demonstrated 20 years ago. It’s enough of a bioterrorism concern that companies carefully monitor who is ordering which genes. But it’s also an important way to respond to a sudden outbreak, since synthetic virus recipes give researchers powerful ways to study treatments, vaccines, and how mutations could make it more dangerous.
When a synthetic virus is better than the real thing
Baric’s North Carolina lab, which specializes in engineering viruses, has previously butted heads with Washington agencies over the work, which has included synthesizing new, never before seen coronaviruses that can infect mice. In 2014, the National Institutes of Health froze funding to several labs, including Baric’s, over concerns that such research was too risky. The funding was later reinstated.
For the China virus, Baric said in a telephone interview, his team placed an order for matching DNA from a manufacturer last month. Their first step was to go online and look at genetic sequences of the virus. They then compared several available sequences, which differ slightly, and picked a “consensus” version to have manufactured. . . .
. . . . The technology immediately created bio-weapon worries. What if terrorists used the technique to resurrect smallpox? That hasn’t happened, but it does mean that scourges like polio, smallpox—and now the Chinese coronavirus—cannot now ever be truly wiped out. Researchers at the US Centers for Disease Control and Prevention (CDC) drove that point home in 2005 when they resurrected the influenza virus that killed tens of millions in 1918–1919. . . .
To keep the technology out of the hands of evil-doers, companies that manufacture DNA banded together a few years ago to limit access to dangerous genes. The big US players have all agreed to compare incoming DNA orders to a database of about 60 lethal germs and toxins called “select agents” so that only authorized labs can ever obtain the DNA needed to resurrect them. . . .
Well, looks like ol’ Dov “Project For A New American Century” Zakheim is advising Herr Trump on invoking the Cold-War monstrosity that is the “Defense Production Act” on order to “augment” civilian hospital’s ability to cope with the coming pandemic:
https://news.yahoo.com/pressure-grows-on-trump-to-invoke-defense-production-act-for-coronavirus-response-004710535.html
Here’s an interesting piece in the Atlantic describing some of what’s been learned about what makes the SARS-CoV‑2 virus that causes COVID-19 different from other coronaviruses known to infect humans. The article mentions some of what we’ve already heard, like how this virus unusually infects both the upper and lower respiratory tracts and describes the biology of why that happens. It turns out the ‘spike’ part of the SARS-CoV‑2 virus is unusually good at latching into a protein called ACE2 which is found on the exterior of the cells in human airways. This ability to latch onto ACE2 is likely a big factor in what has allowed the virus to infect upper airways. It’s thought that the virus likely infects the upper airways first and then, as cells in the airway die and are sloughed off, the virus makes its way down to the lower respiratory tract and lungs where the deadly infections might occur. It’s this pattern of first infecting the upper respiratory tract before making its way down to the lungs that has given the virus the ability to silently spread while it’s in a relatively asymptomatic initial phase before it suddenly turns much more vicious and deadly.
But that ability to latch strongly on the ACE2 protein in human airways is just one of the mutations that has made this virus exceptional at spreading among humans. Another key feature has to do with a protein bridge that connects two halves of the virus’s spike. When the spike gets activate the virus injects its payload into the cell. Activating the spike requires the cleavage of a protein bridge connecting the two halves of the spike and it turns out this protein bridge is cleavable by the enzyme furin which is ubiquitous in human cells. This wasn’t the case for SARS, which had a protein bridge that was less likely to be cleaved. So SARS-CoV‑2 can first latch onto to human upper airway cells more effectively than SARS and once there is readily activated much more easily than SARS.
But here is perhaps the most notable observation made about this virus thus far: it doesn’t appear to be mutation in any meaningful ways. Out of the 100-plus mutations that have been observed in wild so far, none of those viral strains has emerged as a dominant strain. That’s unusually for a virus that apparently only recently jumped to humans and has been spreading at a wild rate. It’s as if the virus is already evolutionarily optimized for spreading among humans and there are no ‘gain-of-fuction’ mutations left for it acquire. As Lisa Gralinski, a coronavirus expert at the University of North Carolina Chapel Hill, described it, “The virus has been remarkably stable given how much transmission we’ve seen...That makes sense, because there’s no evolutionary pressure on the virus to transmit better. It’s doing a great job of spreading around the world right now.” Note that Gralinsky works closely with Ralph Baric’s lab. Recall that Baric is the researcher who constructed a chimeric virus out of a SARS virus and horseshoe bat coronavirus in 2015, so Baric and Gralinski are going to be world leading experts on coronaviruses. They literally build news ones. So when someone like Gralinski observes that the it makes sense that the virus wouldn’t feel any evolutionary pressure to spread more readily because it’s already doing such a good job that’s quite a statement. Evolution doesn’t stop just because it’s already doing a really good job. If there was a mutation that would allow the virus to spread even more readily that would happen. And normally does happen. But it hasn’t happened so for SARS-CoV‑2 because it’s apparently already at some sort of coronavirus evolutionary peak:
“Since the start of the pandemic, the virus hasn’t changed in any obviously important ways. It’s mutating in the way that all viruses do. But of the 100-plus mutations that have been documented, none has risen to dominance, which suggests that none is especially important. “The virus has been remarkably stable given how much transmission we’ve seen,” says Lisa Gralinski of the University of North Carolina. “That makes sense, because there’s no evolutionary pressure on the virus to transmit better. It’s doing a great job of spreading around the world right now.””
No evolutionary pressure to transmit better. It’s already evolved the ability to latch onto ACE2 far more strongly than SARS. And once it latches onto those ACE2 proteins in the upper respiratory tract, the virus is able to activate itself more easily than SARS with the help of a ubiquitous human protein furin that will come along and cleave the spike protein bridge required to activate the virus. Those two evolutionary features appear to be critical for giving this virus its remarkably high levels of infectiousness.
And then we have the obligatory assurances that, despite the seeming improbability of a virus jumping from animals to humans already having the key features that make it seemingly optimized for spreading between people, we shouldn’t jump to conclusions like the obvious possibility that the virus was man-made. Instead, we’re reminded that while the odds of an individual virus acquiring these mutations and then jumping to humans is “very low”, random low probability events do happen. That’s the assurance. A reminder that even the improbable is possible:
And while that’s certainly true that low probability events can indeed happen, that’s not exactly a compelling counter argument to suspicious that the virus was man-made. After all, what’s more improbable: that an incredibly low-probably event happened where this virus just happened to have all of these optimized features for humans when it jumped from another animal vs the probably that it was made in a lab. Which scenario is less likely?
Also keep in mind that, while the large number of viruses that get produced means highly improbably events can realistically happen, let’s not forget that the same principle should apply when it comes to new variants of the virus emerging with new functional mutations. Like a new dominant strain with a mutation that allows it to spread more quickly and become a dominant strain. That’s not happening. Why aren’t those low probably events driving the evolution of this virus? Might the virus already have had its evolution sped up? Don’t forget that the notorious “gain-of-function” experiments involving H5N1 were experiments that sped up the evolution of the virus. That’s how the gain of function was happening. Sped up evolution experiments. So if you just sped a virus’s evolution up long enough with these kinds of experiments would you hit a point where the virus doesn’t evolve anymore and is basically already optimized? Might a lack of viral evolution be an indirect sign that it’s already man-made? Who knows, but it’s worth noting the one silver lining in all this: at least it doesn’t sound like the virus itself will get much worse. Because it can’t get any better.
Here’s a pair of research publications that are just getting released that expand on the observation that SARS-CoV‑2 virus has two key features that causes COVID-19 to be much more infectious in humans than the SARS-CoV virus that cause the SARS outbreak in 2003:
First, recall how SARS-CoV‑2 appears to stick to the ACE2 receptors on the cell walls of human airways much more effectively than SARS-CoV. This helps the virus infect the upper respiratory tract unlike SARS. Also recall how SARS-CoV‑2 has a cleavage site on its spike protein that can be cleaved by the human protein furin. This is seen as crucial for its infectiousness because cleavage of the spike protein is required for the virus to inject its payload into the cell and furin is ubiquitous on the surface of human airway cells. The original SARS-CoV virus from 2003 doesn’t have that furin cleavage site. These are two key features that have made COVID-19 much more infectious than SARS.
So the first publication below expands on how anomalous it is for the SARS-CoV‑2 to possess that furin cleavage site on the spike protein when you look at the entire family of known coronaviruses and the subgroup that SARS-CoV‑2 falls into. The paper uses the label 2019-nCoV for the SARS-CoV‑2 virus (which is the more widely used label), so the naming can get a little confusing.
There are different generas (families) of coronaviruses. SARS-CoV‑2 (2019-nCoV) belongs to the Betacoronavirus family which has different lineages. Click here to see a visualization from the paper of the phylogenetic coronavirus family tree for different coronaviruses in the Alphacoronavirus and Betacoronavirus families. You can see that the Betacoronavirus family has four difference lineages (a, b, c, d). SARS-CoV‑2 belongs to the b lineage, which includes the SARS-CoV virus from 2003. The b lineage also includes the CoV ZXC21 bat virus, which is one of the viruses most closely related to SARS-CoV‑2 which is the major reason for the initial suspicions that the virus jumped from bats to humans.
Now, one would expect SARS-CoV‑2 to be more similar to other viruses in that same lineage than it is to the viruses in other lineages or generas since it’s assumed they emerged from a common ancestor. And for the most part that’s true, with the major exception of that cleavage site on SARS-CoV‑2. It turns out that no other known viruses in that b lineage of Betacoronaviruses possess the furin cleavage site. There are Betacoronaviruses in different lineages that do posses the furin cleavage site, but none in the b lineage. It’s pretty odd.
The authors in the paper speculate that this addition of the furin cleavage site in SARS-CoV‑2 represents a gain-of-function mutation for the virus that allows it to infect humans more efficiently. So why is it that no other coronaviruses in the b lineage of Betacoronaviruses have the furin cleavage site? Well, the authors speculate that this might be an example of convergent evolution taking place between SARS-CoV‑2 and other coronaviruses outside of the b lineage that also possess the furin cleavage sites. Convergent evolution is a well known phenomena in nature where different organisms independently evolve to possess similar features. And if we assume that SARS-CoV‑2 isn’t a man-made virus then convergent evolution is a reasonable suspicion. Of course, in the era of synthetic biology and ‘gain-of-function’ techniques in the lab, that assumption that this isn’t man-made is becoming an increasingly tenuous assumption. More generally, when we have to fall back on assumptions of convergent evolution to explain an apparent gain-of-function adaptation it highlights how unusual SARS-CoV‑2 is compared to its closest viral cousins.
Now, in the second publication below, the authors suggest a different natural mechanism that could have resulted in the evolutionarily unusual SARS-CoV‑2 virus: recombination. That’s a process that can happen in the same animal gets infected by two RNA different viruses at the same time, resulting a new chimerica virus that a combination of the two viral genomes. The authors observe that the genetic sequence of the Pangolin-CoV virus — the coronavirus that infects Pangolins — is the second most similar so SARS-CoV‑2 after the horseshoe bat version. But one part of the the S‑protein (the protein with the furin cleavage site) in SARS-CoV‑2 is actually much more closely related to the S‑protein in Pangolin-CoV than to the horseshoe bat version of the virus. The S‑protein consists of two subunits (S1 and S2) that are generated when the protein is cleaved. The S1 subunit contains the part of the protein that recognizes the ACE2 receptor on mammalian cells. The S1 subunit also contains the furin cleavage site in SARS-CoV‑2, but not Pangolin-CoV. Recall how Pangolins have been suspected to be an intermediate host between bats and humans if we assume this really did jump to humans from the wild. And yet even Pangolin-CoV virus’s S‑protein doesn’t have the furin cleavage site.
The authors try to explain the sudden emergence of the furin cleavage site by suggesting that another coronavirus with a furin cleavage site infected an animal (a Pangolin or bat) at the same time it was infected with the Pangolin or bat coronavirus and that resulted in a recombination even and the insertion of that cleavage site in Pangolin-CoV, resulting in SARS-CoV‑2 (or an intermediate) emerging. And while it’s possible recombination was what led to the sudden addition of precisely the adaptation that allows the virus to infect humans highly efficiently, it’s still a low probability event that we’re talking about. After all, that furin cleavage site is in an S‑protein that’s almost identical between SARS-CoV‑2 and Pangolin-CoV, implying that if a recombination event took place it didn’t change the Pangolin-CoV S‑protein very much. So what are the odds that the change just happened to include this crucial furin cleavage site? That seems like awful luck. Now, if we later discover a coronavirus that has an S‑protein genetic sequence that’s an even closer match to the SARS-CoV‑2 S‑protein sequence and contains that furin cleavage site, well that would make a recombination event scenario more plausible. But unless we find an example of an existing virus with a close S‑protein match it seems like just horrible luck that the furin cleavage site just happened to be part of the mystery coronavirus that got recombined into the bat or Pangolin versions.
Also note that falling back on the recombination explanation is partly appealing in this case between that furin cleavage site is cannonical according to the first article below. It’s like exactly what you would need for furin to latch onto the spike protein and not a less potent variant. We would expect a cannonical cleavage site in a virus that’s had a long time to evolve within a human host. That’s just evolution in action. But in this case it’s like the virus had that evolutionarily optimized site right away, which is why it’s tempting to assume it acquired it from a different virus that already had an evolutionarily optimized site. It’s possible, but really bad luck.
And that appears to be the general theme for explaining the unexpected genetic characteristics of the SARS-CoV‑2 virus causing the COVID-19 pandemic: if this happened naturally, it was a very unlucky turn of events both because of the extreme negative consequences and because of how improbable it was to happen in the first place. That’s not to say that viral pandemics of this nature were improbable. On the contrary, future pandemics are a certainty. It was just a matter of when and how. But having this virus emerge with seemingly optimized genetics for infecting humans without first going through an earlier, less infectious strain, is just horrible luck if that’s what happened.
Now, it’s also possible there was an evolutionary intermediary we just haven’t found yet. For example, let’s say SARS-CoV‑2 really did emerge from Pangolin-CoV. There could have been an earlier version we never detected that had non-cannonical furin cleavage sites that furin could only weakly act upon. Perhaps this hypothetical earlier version of the virus has been infecting people for a while without causing significant symptoms and allowing evolution to play out in the human host. This would be the convergent evolution scenario involving an unknown intermediary. It’s a possible scenario, especially if the weaker version of the virus didn’t really cause significant disease. In that case there wouldn’t have been any reason for doctors to zero in on it and sequence its genome. But so far we have no evidence of that earlier version of this virus floating around. It’s still just a hypothetical.
So when it comes to the question of whether or not this is a man-made virus, we appear to be a situation where we’re forced to guestimate the relative likelihood that this virus could have emerged naturally vs being made in a lab. We know it could emerge naturally. There are known mechanisms for doing that. We also know it could obviously have been built in a lab, which would certainly explain the unexpected characteristics of this virus. Which of those scenarios is most likely?
Ok, here’s the first article in Antiviral Research that describes how the SARS-CoV‑2 virus (2019-nCov) is the only virus in the b lineage of the Betacoronavirus genera with that furin cleavage site. A furin cleavage site that happens to be a cannonical site which means its basically evolutionarily optimized for furin to latch onto. As the authors put it, this represents a gain-of-function for SARS-CoV‑2 (2019-nCov) and since similar furin cleavage sites have been observed in different lineages of Betacoronavirus this may be an example of convergent evolution in action:
“Since furin is highly expressed in lungs, an enveloped virus that infects the respiratory tract may successfully exploit this convertase to activate its surface glycoprotein (Bassi et al., 2017; Mbikay et al., 1997). Before the emergence of the 2019-nCoV, this important feature was not observed in the lineage b of betacoronaviruses. However, it is shared by other CoV (HCoV-OC43, MERS-CoV, MHV-A59) harbouring furin-like cleavage sites in their S‑protein (Fig. 2; Table 1), which were shown to be processed by furin experimentally (Le Coupanec et al., 2015; Mille and Whittaker, 2014). Strikingly, the 2019-nCoV S‑protein sequence contains 12 additional nucleotides upstream of the single Arg↓ cleavage site 1 (Fig. 1, Fig. 2) leading to a predictively solvent-exposed PRRAR↓SV sequence, which corresponds to a canonical furin-like cleavage site (Braun and Sauter, 2019; Izaguirre, 2019; Seidah and Prat, 2012). This furin-like cleavage site, is supposed to be cleaved during virus egress (Mille and Whittaker, 2014) for S‑protein “priming” and may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b betacoronaviruses. This possibly illustrates a convergent evolution pathway between unrelated CoVs. Interestingly, if this site is not processed, the S‑protein is expected to be cleaved at site 2 during virus endocytosis, as observed for the SARS-CoV.”
As the authors put it, the observation of the of an additional 12 nucleotides (encoding for four additional amino acids) that happens to encode for a furin cleavage site right in the S‑protein (the protein that needs to be cleaved for the virus to inject its payload) is striking. It’s striking, in part because it’s not found in the closely related bat coronavirus or any other viruses in the b lineage of Betacoronaviruses. And striking because the furin cleavage site encoded by these 12 nucleotides is the cannonical site. That’s why convergent evolution is proposed as an explanation: it’s one of the natural processes that could explain this striking observation that SARS-CoV‑2 somehow acquired a cannonical furin cleavage site despite the sites’s absence in all of the viruses in the b lineage that the virus is assumed to have evolved from.
But as the second paper below indicates, coevolution isn’t the only possible natural explanation for this striking observation. It’s possible there was a recombination event. That’s what they speculated when observing that the S‑protein of SARS-CoV‑2 — the protein that contains this furin cleavage site — is even more closely related to the S‑protein found in the Pangolin-CoV than the bat version. The Receptor Binding Domain (RBD) of SARS-CoV‑2 and Pangolin-CoV — the parts of the virus that recognize and stick to the ACE2 receptor on human cells — are almost identical. All indication from the genetics make Pangolin-CoV the likeliest known precursor to SARS-CoV‑2. But even with Pangolin-CoV the S‑protein doesn’t have that furin cleavage site. But instead of suggesting the seemingly sudden addition to the furin cleavage site may have arisen through evolution (convergent evolution in this case), the authors speculate that perhaps a recombination even took place where a Pangolin, or some other intermediate host, got infected with both Pangolin-CoV and a different virus with does have the furin cleavage site and SARS-CoV‑2 emerged:
“The CoV S protein consists of two subunits (S1 and S2), mediates infection of receptor-expressing host cells, and is a critical target for antiviral neutralizing antibodies [12]. S1 contains a receptor-binding domain (RBD) that consists of an approximately 193 amino acid fragment, which is responsible for recognizing and binding the cell surface receptor [13, 14]. Zhou et al. experimentally confirmed that SARS-CoV‑2 is able to use human, Chinese horseshoe bat, civet, and pig ACE2 proteins as an entry receptor in ACE2-expressing cells [3], suggesting that the RBD of SARS-CoV‑2 mediates infection in humans and other animals. To gain sequence-level insight into the pathogenic potential of Pangolin-CoV, we first investigated the amino acid variation pattern of the S1 proteins from Pangolin-CoV, SARS-CoV‑2, RaTG13, and other representative SARS/SARSr-CoVs. The amino acid phylogenetic tree showed that the S1 protein of Pangolin-CoV is more closely related to that of 2019-CoV than to that of RaTG13. Within the RBD, we further found that Pangolin-CoV and SARS-CoV‑2 were highly conserved, with only one amino acid change (500H/500Q) (Figure 3), which is not one of the five key residues involved in the interaction with human ACE2 [3, 14]. These results indicate that Pangolin-CoV could have pathogenic potential similar to that of SARS-CoV‑2. In contrast, RaTG13 has changes in 17 amino acid residues, 4 of which are among the key amino acid residues (Figure 3). There are evidences suggesting that the change of 472L (SARS-CoV) to 486F (SARS-CoV‑2) (corresponding to the second key amino acid residue change in Figure 3) may make stronger van der Waals contact with M82 (ACE2) [15]. Besides, the major substitution of 404V in the SARS-CoV-RBD with 417K in the SARS-CoV-2-RBD (see 420 alignment position in Figure 3 and without amino acid change between the SARS-CoV‑2 and RaTG13) may result in tighter association because of the salt bridge formation between 417K and 30D of ACE2 [15]. Nevertheless, further investigation is still needed about whether those mutations affect the affinity for ACE2. Whether the Pangolin-CoV or RaTG13 are potential infectious agents to humans remains to be determined.”
So Pangolin-CoV’s S1 subunit is the most closely related to SARS-CoV-2’s S1 subunit. And that’s the part of the S‑protein that contains the furin cleavage site in SARS-CoV‑2 but not in any other b lineage Betacoronaviruses. But the furin cleavage site is found in more distantly related coronaviruses. That’s why the authors suggest SARS-CoV‑2 may have arisen from a recombination event:
Might we be dealing with a virus that’s a consequence of really bad evolutionary luck? If we assume this virus arose naturally then those are the kinds of scenarios we need to assumed happened. Really bad luck scenarios.
A man-made virus could also be seen as a differnt kind of really bad luck scenario although that’s not really luck. It’s just really bad. Luck doesn’t have that much to do with it. So what’s more likely: a really bad luck natural scenario or a really bad no-luck-involved man-made scenario? That’s kind of the meta question involved year. Grant, if this is a man-made scenario we have gotten very lucky so far in that that virus hasn’t mutated into something worse as it blows up and spreads across the globe. Although that lack of observed evolution appears to have more to do with the virus already being optimized for spreading among humans, which is pretty bad as far good luck goes.
@Pterrafractyl–
It is important to remember that this did NOT occur in a vacuum, but in the context of a full-court press destabilization effort against China, headed by white nationalist Steve Bannon, whose primary political/philosophical reference is Julius Evola. Evola originally liked Mussolini, but thought he was too soft and gravitated to the Nazi SS, who financed his work by the end of the war. https://spitfirelist.com/for-the-record/ftr-947-evola-on-our-minds/
In July of last year, Bannon said ” . . . . ‘These are two systems that are incompatible,’ Mr. Bannon said of the United States and China. ‘One side is going to win, and one side is going to lose.’ . . . .”
https://www.nytimes.com/2019/07/20/us/politics/china-red-scare-washington.html
That is a declaration of totaler krieg–total war!
The “bad luck” hypothesis reminds me of “The New York Times’s” reaction to the Dallas Police Department dictabelt recording that indicated at least four shots fired in Dealy Plaza on 11/22/1963, thereby disproving the Warren Commission’s hypothesis.
They opined that this simply meant that there were two, apparently unconnected “lone nuts” at work in Dallas on that day.
Now that is REALLY bad luck, indeed!
In the age of gene editing, “bad luck” doesn’t cut it.
Using recombinant DNA in an intermediate host could very easily be engineered as well.
More on that in a minute.
Best,
Dave
@Pterrafractyl–
Note that the “pangolin-host research” falls in line with some of the DARPA-funded research Whitney Webb discusses:
https://spitfirelist.com/news/disturbing-article-about-darpa-and-bat-borne-coronaviruses/
” . . . . .For instance, DARPA spent $10 million on one project in 2018 ‘to unravel the complex causes of bat-borne viruses that have recently made the jump to humans, causing concern among global health officials.” Another research project backed by both DARPA and NIH saw researchers at Colorado State University examine the coronavirus that causes Middle East Respiratory Syndrome (MERS) in bats and camels ‘to understand the role of these hosts in transmitting disease to humans.’ . . . For instance, one study conducted in Southern China in 2018 resulted in the discovery of 89 new “novel bat coronavirus” strains that use the same receptor as the coronavirus known as Middle East Respiratory Syndrome (MERS). That study was jointly funded by the Chinese government’s Ministry of Science and Technology, USAID — an organization long alleged to be a front for U.S. intelligence, and the U.S. National Institute of Health — which has collaborated with both the CIA and the Pentagon on infectious disease and bioweapons research.. . . .”
Damn, what bad luck!
There’s an analysis of the SARS-CoV‑2 virus published a Nature Medicine a couple weeks ago that claimed to have conclusively proven that the virus couldn’t have emerged from a lab. It didn’t actually remotely prove that but the letter is still noteworthy for a number of very interesting observation about the nature of the virus and its origins. In particular, the authors note the two key features of the virus that others have observed that make it so unusually infectious: 1. The high affinity the virus’s Receptor Binding Domain (RBD) has for the human ACE2 receptors found in the respiratory tracts of humans are other mammals (like ferrets). And 2. The cleavage site in the S‑protein of the virus that allow the human protein furin to cleave the virus which triggers the release of its viral payload into the cell.
As we’ve seen and as the authors note, that cleavage furin site is a canonical human furin cleavage site — so human furin is very good at cleaving it — and hasn’t been found in any other viruses in the “b lineage” of the betacoronavirus family so from an evolutionary perspective it’s a surprise to see it in this virus. But SARS-CoV‑2 RBD that binds to ACE2 is not, however, and that’s what the authors are relying on to make their claim that it couldn’t possibly have been created in a lab. As the authors note, the models researchers use to predict whether or not a viral RBD would be effective at allowing it to bind to the ACE2 receptor actually predict that the RBD in SARS-CoV‑2 wouldn’t be effective at binding ACE2 and that’s the basis for their conclusive claim that it couldn’t have been developed in a lab.
That is, of course, a nonsense form of analysis because it assumes the only techniques used in labs to create more potent forms of viruses rely on first deducing what an optimal viral protein sequence would be an directly creating a viral genome to encode for that sequence. And as we saw, most notably in the ‘gain-of-function’ experiments involving H5N1 avian flu in ferrets, those researchers didn’t need to have a particular viral sequence in mind when creating their improved form of the virus. They sped up evolution and let evolution take care of coming up with the optimal sequence. Specifically, in that now-notorious experiment, they used three strains of H5N1: one unmodified native strain and two strains that had modifications known to make influenza more virulent. They then took those strains and successively passed the virus from ferret to ferret. After ten passages, the strains that started off with the modifications had acquired the ability to be passed from ferret to ferret through the air, although the native unmodified H5N1 strain hadn’t acquired that ability. But, crucially, all three strains — modified and unmodified — acquired a particular novel mutation that the researchers hadn’t known about and it was presumed that this mutation was was allowed the modified strains to now spread in the air. It was an example of simple experiment that allowed researchers to create a new strain in the lab with new abilities without knowing in advance the protein sequence required to confer those abilities.
So when the researchers in the following Nature Medicine letter conclusively conclude that there’s no way the SARS-CoV‑2 virus could have been developed in a lab because the SARS-CoV‑2 RBD that has an unusually high affinity for ACE2 wouldn’t have been predicted by existing models, that’s a conclusion that appears to completely ignore the existence of these ‘gain-of-function’ experiments involving the passage of viruses from animal to animal. And yet they actually refer to such experiments in the letter and point out that we can’t conclude that the virus didn’t emerge from a lab precisely between there are so many documented cases of SARS-CoV-like viruses getting worked on in biosafety labs around the world in cell culture and/or animal models and accidentally escaping. Yep. In the very piece that claims to conclusively conclude that the virus couldn’t have been engineered, they point out that SARS-CoV-like viruses have been worked on in cell cultures and animal models in labs around the world for years. So it’s a very confusing letter in that respect. They appear to have argued that the virus couldn’t have been engineered but may have originated from a lab.
There’s another feature of the virus they point to as evidence that it couldn’t have been developed in a lab that also completely ignores these animal passage experiments. They point out the furin cleavage site is preceded by a proline amino acid. And that proline — which creates a strong twist in the protein — predicts the existence of O‑linked glycans around the cleavage site which is exactly what is found. The authors point out that O‑linked glycans are only going to be developed in the presence of an immune system and therefore the virus couldn’t have evolved from a cell culture environment. And while that may be true, it completely ignores animal passage experiments where the animals’ immune systems would obviously be involved in the evolution of the virus. It’s also worth point out that animal passage experiments would explain the furin cleavage site that isn’t found in any of the other b lineage betacoronaviruses. At least if the experiments were done in an animal with a human-like furin. Something put that furin cleavage site there. The authors specifically raise the possibility of animal passage experiments being used but assert that it would have required a progenitor virus with a very high sequence similarity to SARS-CoV‑2 and no such progenitor virus has been observed. This, again, ignores how that landmark 2011 ‘gain-of-function’ experiment with H5N1 in ferrets “included the use of man-made viruses as a starting point. In some experiments they used native H5N1 and in others they used man-made viruses with modifications known to make influenza more virulent. So the lack of any known progenitor viruses as a starting point for an animal passage experiment as some sort of proof that the the virus couldn’t have been made in a lab completely ignore that the progenitor virus could also have been made in a lab.
After concluding that the virus couldn’t possibly have been generated in a lab, the authors speculate about two possible scenarios for a natural origin of the virus: that the virus evolved these unusual characteristics before it jump to humans or after it jumped to humans. If we consider the first scenario — that the virus acquired these unusual characteristics that make it optimal for spreading between humans in an animal before jumping to humans — the authors simply point out that the full range of virsues in bats and pangolins is very undersampled and so while we don’t know of any bat or pangolin coronaviruses with furin cleavage sites we don’t know they don’t exist. And then they point out that the virus would have had to evolve in an animal with an ACE2 receptor similar to humans. So the authors are basically saying it’s possible that the virus could have acquired the characteristics that make it highly infectious in humans before it actually made the jump.
The authors’ conclusion about second scenario — that it evolved these characteristics after jumping to humans — is where they make an important point about the possible origins of this virus: it’s very possible the progenitors to SARS-CoV‑2 had already been circulating in humans and that’s how a virus optimized for spreading to humans suddenly emerged. It’s a very feasible scenario and it doesn’t involve the virus being developed in the lab at all. It’s also worth noting that this would be consistent with the theory put forth by some Chinese researchers that there are two distinct strains — the ‘L‑type’ and ‘S‑Type’ strain — where the ‘S‑type’ strain was an older but less virulent strain that had been circulating for a while before an ‘L‑type’ strain emerged near Wuhan that caused the spike in deaths. One of the authors of the following Nature Medicine letter, Andrew Rambaut, is one of the people who took strong issue with the analysis by those Chinese researchers. Rambaut now appears to be very open to the idea that there was some sort of much less virulent early version of SARS-CoV‑2 that would circulating between humans for years, giving the virus time to develop the features that allow it to spread so effectively.
In the following Science Alert article that describes this research, it includes a blog post by Francis Collins, the head of the US National Institutes of Health (NIH), highlighting the Nature Medicine letter. In that post, Collins points out that the progenitor virus could have been circulating for years or decades in humans, giving it time to evolve these characteristics for better human transmission. But it’s worth noting the remarkable coincidence if its the case that a less virulent form of the virus has been spreading around for years: if it’s been spreading for years or decades, the present day super version could have presumably spread around the world and therefore emerged anywhere in the world. And yet it just happened to emerge in China, the country where the initial animal-to-human jump could would most likely have taken place. Right at this time when there’s a big Chinese destabilization campaign taking place. That’s some interesting luck.
Ok, here’s a piece about that Nature Medicine letter that included an interview of some of the authors. And its in that interview where the authors point out that the scenario that assumes the virus first jumped from animal to human before acquiring all of these features makes it possible that earlier weaker forms of the virus have been floating around for years or decades:
““By comparing the available genome sequence data for known coronavirus strains, we can firmly determine that SARS-CoV‑2 originated through natural processes,” said one of the researchers, immunologist Kristian Andersen at Scripps Research.”
By comparing the available genome sequence data for known coronavirus strains, we can firmly determine that SARS-CoV‑2 originated through natural processes. That was the conclusion of this letter. As we’ll see, that’s a highly suspect conclusion that completely ignores animal-passage experiments. But if we assume it wasn’t created in a lab, that leaves two general scenarios: it either evolved these characteristics before jumping to humans or after humans. If that happened before jumping to humans it would assume the existence of a virus that’s never been observed. And it’s entirely possible there’s a virus in animals with these remarkable characteristics that have never been observed since the diversity of coronaviruses in animals is very undersampled. But if we assume this came from bats or pangolins, it’s notable that none of the known coronaviruses in those animals have these characteristics because such characteristics wouldn’t actually help the virus spread in those animals:
Then there’s the hypothesis that it jumped to humans, perhaps years or decades ago, and evolved his characteristics at that point within human hosts. That seems like a much more plausible scenario. But it’s a scenario that suggests this virulent human-optimized form of the virus could have erupted anywhere. And yet it happened in China, the location that would have been the primary suspect for a recent animal-to-human jump. What are the odds of that?
Ok, now here’s the actual Nature Medicine letter:
“The genomic features described here may explain in part the infectiousness and transmissibility of SARS-CoV‑2 in humans. Although the evidence shows that SARS-CoV‑2 is not a purposefully manipulated virus, it is currently impossible to prove or disprove the other theories of its origin described here. However, since we observed all notable SARS-CoV‑2 features, including the optimized RBD and polybasic cleavage site, in related coronaviruses in nature, we do not believe that any type of laboratory-based scenario is plausible.”
They just don’t see any type of laboratory-based scenario as plausible. That’s what they concluded. For rather odd reasons.
First, they note the two key features of SARS-CoV‑2 that make it so infectious in humans: the virus appears to be “optimized” for binding to human ACE2 receptors. And the insertion of a furin cleavage site. A cleavage site that also has the predicted addition of O‑linked glycans flanking it that help the virus elude the immune system. How those two key features emerged in this seemingly new virus remains the big mystery:
First, regarding the seemingly optimized receptor binding domain that allows the virus to bind to the human ACE2 receptor, the authors note that the SARS-CoV‑2 RBD would NOT have been predicted based on models. That alone is why the authors assume it couldn’t have been built in a lab. It’s a conclusion that also assumes the virus could only have been built in a lab by intentional design, as opposed to using animal passage ‘gain-of-fuction’ experiments:
Then the authors look to the furin cleavage site. They note that no other known betacoronaviruses in the b lineage have this feature, but since it’s a known feature in other coronaviruses they suggest that it’s likely we’ll find viruses with partial or full furin (polybasic) cleavage sites in other species. That’s it. Remarkably, they actually note that similar cleavage sites were acquired during animal passage experiments using avian flu:
The authors note that the O‑linked glycans flanking the cleavage site might be used for evading the immune system but that unclear. They later discuss the possibility that the virus could have emerged from animal passage experiments, noting that such experiments have been taking place on coronaviruses in labs around the world for years. And while they acknowledge the possibility that the virus’s optimized novel RBD for the ACE2 receptor emerged from such experiments, they find the idea that it evolved naturally far more parsimonious. Why is it more parsimonious? Who knows. There’s no explanation for that:
Then they note that the acquisition of furin cleavage sites an O‑linked glycans has been observed in animal passage experiments with avian flu, and point out that this is an argument against the virus being developed in a cell culture. Well, yeah, but what about animal passage experiments? Well, they suggests that, yes, it’s possible. But such experiments would have required a viral progenitor that is close enough to the SARS-CoV‑2 sequence to be a viable starting point and such viruses haven’t been described. It’s an explanation that completely ignore the obviously possibility of a man-made starting point. They they point out that the animal passage experiments would have had to take place in animals with ACE2 receptors similar enough to humans (like ferrets!!) and note that no such research has been described. So they are literally dismissing the animal passage experiment possibility because the people who hypothetically carried it out didn’t publicly report it:
So that was the recent Nature Medicine letter that apparently ‘proved’ the virus couldn’t emerge in a lab. A letter that, if read closely, based its firm conclusions on the notion that if it was developed in a lab it would have been reported by the people who did it. The optimized RBD for ACE2, the furin cleavage site, and the O‑linked glycans all appear to be features that could be very plausibly explained by animal passage experiments. But because specific animal passage experiments demonstrating the acquisition of these features by a closely related progenitor virus haven’t been publicly reported that means would should assume they didn’t happen and therefore we can rule out animal passage experiments as a plausible source. An implausibly bad argument about plausibility. That’s the cutting edge of analysis on this virus. Yikes.
@Pterrafractyl–
This article is worthless–ANY virus can be made in a laboratory, as the “MIT Technology Review” article from 2/15/2020 reminds us.
Claims that trumpet “the virus wasn’t made in a laboratory” are more than a little suspect–they not only ignore the state of the art of virology but ignore the destabilization effort against China and the DARPA research into Chinese bat-borne coronaviruses.
I will be addressing this in a program to be recorded shortly.
https://www.technologyreview.com/s/615231/biologists-rush-to-re-create-the-china-coronavirus-from-its-dna-code/
Note also, the first article from this May, 2001 broadcast:
https://spitfirelist.com/for-the-record/ftr-282-a-shot-in-the-dark-designer-genes-the-aids-vaccine/
“No Longer Science Fiction! Racially-Targeted Weapons May Become Reality Soon;” Reuters; 1/21/1999.
Best,
Dave
Intelligence report warned of coronavirus crisis as early as November: Sources
“Analysts concluded it could be a cataclysmic event,” a source says.
By
Josh Margolin
and
James Gordon Meek
April 8, 2020, 1:01 AM
10 min read
As far back as late November, U.S. intelligence officials were warning that a contagion was sweeping through China’s Wuhan region, changing the patterns of life and business and posing a threat to the population, according to four sources briefed on the secret reporting.
Concerns about what is now known to be the novel coronavirus pandemic were detailed in a November intelligence report by the military’s National Center for Medical Intelligence (NCMI), according to two officials familiar with the document’s contents.
The report was the result of analysis of wire and computer intercepts, coupled with satellite images. It raised alarms because an out-of-control disease would pose a serious threat to U.S. forces in Asia — forces that depend on the NCMI’s work. And it paints a picture of an American government that could have ramped up mitigation and containment efforts far earlier to prepare for a crisis poised to come home.
“Analysts concluded it could be a cataclysmic event,” one of the sources said of the NCMI’s report. “It was then briefed multiple times to” the Defense Intelligence Agency, the Pentagon’s Joint Staff and the White House.
“The timeline of the intel side of this may be further back than we’re discussing,” the source said of preliminary reports from Wuhan. “But this was definitely being briefed beginning at the end of November as something the military needed to take a posture on.”
https://abcnews.go.com/Politics/intelligence-report-warned-coronavirus-crisis-early-november-sources/story?id=70031273
[ed. note: This may serve as further circumstantial evidence to support the thesis developed in this set of programs regarding the origins of this virus. It seems worth noting that the first reported cases did not reach the public attention until 31 December, while this article from the Business Insider website mentions ‘Late November’ as a possible time in which this virus first began to spread. The prescience of the US military-intelligence establishment seems notable, if not “remarkable.”]
It seems reasonable to suggest that this intel report was suppressed in order for the US intelligence apparatus to maintain a cover of ‘plausible deniability.’
If the US intel apparat was aware of and providing intelligence assessments on a virus that not even the Chinese government realized was a new and deadly strain of an old nemesis, it would suggest at the very least, prior knowledge of the actual lethality/severity of this “novel” virus. It would also lend credence to the claims advanced in the TV Ahashi segment regarding the North American provenance of the 5 previous strains which apparently were combined to produce this monster. It may well be that the timing of this release (ie, 1 o’clock in the morning) was deliberately chosen to serve as a means of burying the story in the same way that publication on a Friday evening would. Just my two Kopek’s worth- Ovid19]
There was a potentially significant study out of China about COVID-19 that could have big implications for the future impact of the virus and how long the current global lockdown period might last. The study is just a preliminary study on a relatively small sample of 175 patients Shanghai Public Health Clinical Centre who had previously suffered from relatively mild cases of COVID-19 and recovered.
Alarmingly, they found that almost a third of the patients had surprisingly low levels of COVID-19 antibodies, with 10 of the patients having such low levels that they couldn’t be detected. Intriguingly, these patients with little to no antibodies skewed towards the younger patients. So the demographic that appears to be least impacted by the virus also has a propensity to have a fleeting antibody response if at all. It’s suggested by the researchers that individuals with no detectable antibodies may have successfully fought off the disease using a different more general immune response that didn’t require the use of antibodies at all.
If this study pans out and there really is a substantial number of primarily younger people who are fighting it off the disease without an meaningful buildup of antibodies, it points to a potentially serious complication with the hopes of using a vaccine to eventually control this pandemic and prevent future pandemics. Because if a third of the populace doesn’t respond to the virus by building up antibodies it’s possible a vaccine won’t actually work for them either:
“All of the patients had recently recovered from mild symptoms of the disease and most of those with low antibody levels were young. The researchers excluded patients who had been admitted to intensive care units because many of them already had antibodies from donated blood plasma.”
A third of recovered patients have unexpectedly low levels of antibodies and most of those people were the young, the one group that appears to be the least impacted by it. This is turning out to be quite a virus.
Does this mean that around 30 percent of people will be prone to reinfection after recovery? Maybe, but since that 30 percent is mostly young it will at least thankfully be the group least likely to be killed by the virus who keep getting reinfected. But that risk of reinfection could still pose quite a risk to the overall strategy of ‘flattening the curve’ with social distancing and locking the global economy down with the hope of slowly building up “herd immunity” while we wait for a vaccine to be developed:
Also keep in mind that there have indeed been a handful of reported cases of people catching COVID-19, recovering, and then catching it again. A women in Japan reportedly caught it a second time over a few weeks after initially recovering, although it’s unclear if that’s what really happened and some experts point towards other explanations. And late last month, there were concerns about the accuracy of COVID-19 tests in Wuhan after a number of people who recovered and had tested negative suddenly tested positive again. Was this a problem with test kits? Or people actually catching the disease a second time?
The above study also raises the question about the employment status of people who can’t develop antibodies and how to restart economies if a substantial percent of the populace can’t develop this immunity. While most of the people in that 30 percent group were relatively young, what about the elderly in that group? Will vaccines work on them? Are they just going to be forced into some sort of permanent quarantine or continually risk exposure to a virus they can’t develop immunity for? And are the young people who currently aren’t developing antibodies going to eventually develop antibodies to future versions of this virus as they get older? We’ll find out. More studies are clearly necessary. But if the finding in the study — that 30 percent of people weren’t producing antibodies at levels high enough to protect against future infections — is accurate the whole world is going to find that out sooner or later. Presumably via waves of reinfections.
ASIA
South Korea’s New Coronavirus Twist: Recovered Patients Test Positive Again
Doctors believe that the disease may have gone dormant and then come back, posing more challenges for testing
By Dasl Yoon and Timothy W. Martin
April 17, 2020 1:40 pm ET
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TEXT
SEOUL—More than 160 South Koreans have tested positive a second time for the coronavirus, a development that suggests the disease may have a longer shelf life than expected.
https://www.wsj.com/articles/south-koreas-new-coronavirus-twist-recovered-patients-test-positive-again-11587145248
Here’s a set of stories about the ongoing clinical trials of Gilead’s remdesivir drug as a COVID-19 treatment. It sound like the high hopes of remdesivir just got dashed but as we’ll see, even if those hopes pan out there’s still almost no way enough remdesivir could be manufactured to meet global demand anyway. It’s a story that also potentially ties into the larger issue of the use of the COVID-19 pandemic to manipulate the stock market for massive profits:
There’s been a number of reports over the past couple of weeks giving hints of how remdesivir has performed in the various clinical trials currently underway. Last week we learned from STAT news that a study at the University of Chicago on 115 COVID-19 patients — 113 with a severe case — appeared to be pretty positive. Severe fevers were receding and nearly all patients were being discharged from the hospital in less than a week. It was the kind of report that didn’t just trigger a surge in Gilead’s stock price but appeared to literally trigger an broader stock market rally on hopes that the drug could alleviate the economic shutdowns.
But that University of Chicago study wasn’t a randomized controlled clinical trial, the gold standard for determining the efficacy of a drug. Well, STAT news just issued a report on the leaked initial findings of a randomized controlled trial in China and the results are a lot less positive than than U of Chicago study. The study was also of severely ill patients and found no statistical significance between the group given the drug and the control group. So that’s a pretty massive blow the hopes of remdesivir.
As the article notes, this isn’t the final word on the topic because there are more studies underway. In addition, the results are being somewhat dismissed by optimists because the study was ended early due to people dropping out. Still, the general lack of optimism over the results appears to be shared by the broader markets, with a global stock slump on Friday being attributed in part to these negative trial results. So we’re seeing how potentially powerful the news of these trial results are in moving financial markets.
Interestingly, the latest negative report is just a initial draft of the report that was apparently accidentally publicly released by the World Health Organization (WHO) on their website and subsequently removed. So someone could have made some good money shorting Gilead’s stock if that leak wasn’t an accident.
Another interesting angle that relates to financial markets is that the results turn out to be the opposite of what biotech analyst at Evercore ISI biotech analyst Umer Raffat had previously been telling investors to expect. The study found that patients on remedisivir actually recovered slightly more slowly than the control group. Raffat had told investors to expect the opposite. Keep in mind this leaked report on the WHO website was just a rough draft so it’s possible we’ll see that flipped in the final report. But as the following article notes, whether or not remdesivir speeds up or slows down recovery is beside the point because the differences between the two groups were statistically insignificant. So, to some extent, it doesn’t really matter from an investment standpoint whether or not remdesivir slightly sped up or slightly slowed down the recovery time. But markets are still driven by psychology and hearing that remdesivir actually slightly harmed patients will have a very different impact on Gilead’s stock than a report that it slightly helped patients.
So following the report of very positive remdesivir preliminary results last week (and subsequent stock rally) we get a WHO leak that shows remdesivir does nothing to help and might actually hurt patients. It’s been quite a week for Gilead investors...and anyone hoping for an actual drug to treat this pandemic:
“Many studies are being run to test remdesivir, and this one will not be the final word. Results are expected soon from a Gilead-run study in severe Covid-19 patients, although that study may be difficult to interpret because the drug is not compared to patients receiving only standard treatment. Encouraging data from patients in that study at the University of Chicago were described by researchers at a virtual town hall and obtained by STAT last week. However, unlike those data, these new results are from a randomized controlled trial, the medical gold standard.”
How do we weigh these conflicting results between last week and this week? By weighting the randomized controlled trial more heavily, that’s how. Which is why this leak was so devastating to those putting their hopes on remdesivir:
And it wasn’t just that there was no statistically significant improvement. The remdesivir actually appear to slightly slow down patient recovery. Although, again, given the lack of statistical significance we can really just conclude that there’s no difference. And yet Evercore ISI investment advisor had previously been telling clients to expect the opposite of a slight decrease in recovery time for the remdesivir group. So there might be something something weird going on here that has yet to be resolved:
Ok, now here’s a Motley Fool article that was published a day before that WHO leak, so the negative results hadn’t been reported yet. Instead, the article is based on the optimism of the U of Chicago story from last week and tries to answer the question of whether or not it’s at all feasible for Gilead to increase drug production at sufficient levels if the drug is eventually proven to be effective. And as the article describes it, there’s just no realistic way Gilead can increase the production of the drug to meet the immediate need. Of course, if remdesivir does end up being approved for COVID-19 treatment a lack of adequate supply doesn’t mean that Gilead wouldn’t profit wildly it. If anything, the company could charge even more for the drug, limiting it largely to wealthy individuals and countries. And that’s why optimism over remdesivir should primarily be optimism held by Gilead’s shareholders and the wealthy:
“But proving remdesivir is a safe and effective COVID-19 treatment (which hasn’t happened yet) is only the first step. Gilead Sciences must secure supply chains, ramp-up manufacturing capacity, and distribute the drug throughout the world. That might prove more difficult than investors realize.”
Yep, proving effectiveness is only the first step. Then you have to actually manufacture the stuff en mass and that’s much easier said than done:
And now here’s an article in Chemical & Engineering News that gives a few more details on the logistics of manufacturing complex pharmaceuticals. It sounds like Gilead initially took 9–12 months to manufacture a new batch of the drug. That’s right, up to a year to create a batch from scratch. But in light of the current pandemic the company said in January that it reduced the timeline to 6–8 months. And keep in mind that Gilead isn’t going to mass produce this stuff unless it’s already been approved for COVID-19 treatment. So based on Gilead’s own guidance it would be 6 months at best before the drug could be produced in large volumes if the world suddenly decides that remdesivir is the go-to- COVID-19 drug. But as we just saw, there’s no realistic way the necessary volume of the drug could be created in time due to the global logistics and limited supplies of rare precursor chemical inputs. And as the following article describes, there’s another factor that could limit Gilead’s ability to produce remdesivir in large volumes: COVID-19. Yes, the virus itself could complicate this process significantly. Why? Because the manufacture of pharmaceuticals is now based on global supply chains, where the sequential steps in the synthesis of the drug is done by different subcontractors around the globe (e.g. hire company A to convert the starting compound to an intermediate compound. then hire company B to convert the intermediate compound to a different intermediate compound, etc). And putting together a global supply chain is a lot harder now that the global economy is shut down:
“As the scope of the pandemic widens, Gilead has been open about the challenges of manufacturing the drug. The firm says it typically takes 9 to 12 months to make an antiviral like remdesivir, but that since January it has shrunk the timeline to 6 to 8 months. “We continue to work on optimizing the chemical synthesis processes,” the company states.”
6–8 months at best. That’s the optimists’ timeframe for creating new batches of the drug. And even Gilead’s own estimates of how much it could increase its manufacturing volume bey the end of the year could be dwarfed by the global need:
And that optimistic project by Gilead assumes COVID-19 itself doesn’t disrupt the setting up of that supply chain, which is a pretty huge assumption:
So as we can see, the one drug that authorities have been most actively pushing as the likeliest miracle treatment that could allow the world to reopen (not counting President Trumps bizarre pushing of hydroxychloroquine) is a drug that effectively can’t be used to treat the world in time. Even if it’s an effective treatment it can’t possibly be an effective solution. At best, remdesivir could be used to treat a lucky subset of patients who happen to get access to the limited supplies.
Also note that we’ve heard virtually no updates about the other promising treatments that have been reported on like the “Thai cocktail” or OyaGen’s Oya1 compound. Who know why there continues to be zero interest in these seemingly promising treatments but that lack of interest is still the case. In the mean time, there’s always bleach.
‘Tis the season of Gilead news: there was a pair of updates about two different COVID-19 trials of Gilead’s remdesivir drug on Wednesday. These were the third and fourth preliminary updates from a Gilead trial in the last week or so. The new reports were broadly trumpeted as positive news. So positive the financial markets rallied in response. As we’re going to see in the following articles, it’s really more ‘good-ish to bad-ish’ news. Good-ish to bad-ish news that nonetheless managed to triggered a rally in the financial markets:
The preliminary reports released Wednesday involved two large ongoing clinical trials of remdesivir. One of the trials is being conducted by the US National Institute of Allergy and Infectious Diseases (NIAID). The other is run by Gilead itself.
When completed, the Gilead study will involved 6,000 COVID-19 patients undergoing treatments from 152 clinical trials from around the world. The preliminary results we heard about last week from the University of Chicago involving 115 patients that indicated that the drug was helping patients recover more rapidly was one of the sites from this larger 6,000 person study. The new preliminary update from Wednesday is based on 400 people.
As we’ll see, it turns out the Gilead study is designed without any control group so the question of how much remdesivir actually helps sick patients (or doesn’t help) systematically can’t be answered by that study. Yep. Due to a lack of a control group, the study instead focuses on just answering the question of whether or not the recovery times for patients differs between groups receiving a 10-day course of the drug vs a 5‑day course. The patients were severely ill but not on ventilators when enrolled in the study (so the patients that need the drug most weren’t tested). The preliminary results released Wednesday suggest there is no difference between the recovery times for the two groups. Now, the positive way to interpret those results is that it indicates patients will receive the benefits for remdesivir with just half the dosage in half the time. It would double the number of patients who could receive the drug. But there’s a far worse possible interpretation of the results: there’s no difference in recovery times because the drug wasn’t actually helping patients recover. Because there’s no control group we can’t know which of those scenarios we’re looking at.
The NIAID study was fortunately a randomized controlled trial that used placebos so basic questions about whether or not the drug actually helps patients. Based on the results from 800 severely ill patients, yes, there appears to be a modest benefit in the form of more rapid recovery times vs the control group. The study found patients on remdesivir recovered in 11 days vs 15 days for the group getting the placebo, a 31% decrease. So based on those results it does appear that remdesivir is helpful, just not nearly as helpful as people were hoping. Crucially, the mortality rates between the case and control groups were statistically insignificant. So while this preliminary result does seem to indicate that remdesivir speeds up recovery time, there’s no evidence yet it actually helps prevent patients from dying. We are also warned that, because these results are preliminary, it’s possible the observed decreased recovery time won’t pan out in the final analysis.
It’s also important to recall that the NIAID preliminary results contradict the findings of the clinical trial conducted in China that found no statistical difference in the recovery times of patients on remdesivir. As the following article notes, that study was also was published in Lancet on Wednesday. So there really was a flood of news about remdesivir on Wednesday. A flood of very mixed news. And that’s why the two preliminary reports can really only be described as good-ish/bad-ish. The reports certainly weren’t what people were hoping for but they could have been worse because they were largely inconclusive:
“During an appearance alongside President Trump in the Oval Office, Anthony Fauci, the director of NIAID, part of the National Institutes of Health, said the data are a “very important proof of concept” and that there was reason for optimism. He cautioned the data were not a “knockout.” At the same time, the study achieved its primary goal, which was to improve the time to recovery, which was reduced by four days for patients on remdesivir.”
It’s not a knockout but there’s reason for optimism. That’s the positive way of spinning these results. Results that showed now statistically significant difference in the mortality rates of these patients:
And note one of the possible end results of these trials: we might discover that remdesivir is most helpful when taken early on before the cases get severe. And because the drug is delivered intravenously, patients need to be in the hospital to receive the drug. So if remdesivir ends up being the only drug found to be helpful against COVID-19 but it’s only helpful if you start it early on in the illness that’s a recipe for sticking almost all moderately ill patients on the drug as a kind of preventive measure. And this, again, is a drug that can’t possibly be made in adequate supplies in short order to meet global demand so the price of the drug during this kind of scenario could just skyrocket:
And then there was the release of the preliminary Gilead study results. No differences in recovery times were found between 5 and 10-day treatments, but whether that’s due to the drug not actually improving patient outcomes can’t be determined because there’s no control group. Gilead created a clinical trial that can’t answer the question of whether or not its drug actually helps:
Finally, there’s the publication of the study out of China that appeared to contradict the NIAID findings: there was no significant difference in the time to clinical improvement, mortality, or viral clearance times:
Ok, now here’s a STAT News excerpt that goes into more of the concerns about the Gilead study design. Concerns that include worries that the study will ultimately just muddy the waters about our understanding of drug’s efficacy. The article also gives Gilead’s explanation for why they left out a control group: due to the limited supplies of the drug the company decided to prioritize on producing more of the drug itself rather than a placebo control. It’s an explanation that only makes sense of producng placebo doses was somehow a significant technical challenge. They also gave the explanation that, due to the deadliness of the disease for severe cases, many families wouldn’t agree to enrolling their relatives in a trial that included the possibility of a placebo. Which, again, is a somewhat odd explanation since that dilemma of distributing placebos to patients that could benefit from the drug would presumably apply to randomized controlled trials for any potentially deadly condition. Plus, if the choice is between enrolling your family member in a trial that involves placebos vs not enrolling your family member in any trial it seems like enrolling in the trial is still going to be a tempting option. And that’s part of the bad-ish news coming out of these trials: Gilead designed a study that couldn’t possibly answer the question of whether or not their drug improved clinical outcomes and then gave very questionable answers for why that happened:
“But outside experts in clinical trial design worry that the results, instead of leading to a clear picture of whether the medicine is effective, will instead muddy the waters further.”
Wouldn’t that be lovely: a 6000 person study that only ends up muddying the waters further. That could literally be what happens as a result of this study design. And as the article notes, there is another Gilead study that does include a control group but only for less sick patients, and even in that case there’s no placebo. Now, the lack of a placebo is certainly problematic, but at least this other study on less sick patients bothered to include “controls” in the form of people not receiving the drug but otherwise getting standard treatment. And that raises the obvious question of why Gilead didn’t do the same thing with this study of severely ill patients?! Yes, lacking a placebo for the controls wouldn’t have been ideal but it certainly would be better than no controls at all. It’s not as if there’s a shortage of severely ill patients who could serve as controls:
And those questions about why Gilead didn’t simply include non-placebo controls aren’t exactly addressed by Gilead’s explanation, other than to suggest that people might not want to be enrolled in a trial where they might be in a group that doesn’t receive the drug. That was so doubt a complication, especially for severely ill patients who could have their life saved from the drug. But, again, it’s not like this conundrum is new. This how randomized controlled clinical trials work: one group gets the drug and one doesn’t:
Next, regarding the possibility that remdesivir could end up being a drug recommended for less sick patients, note how financial analyst Umer Raffat suggested that Gilead’s study of the 6000 patients is establishing exactly that: that remdesivir should be given to less sick patients earlier before they get severly sick, pointing out a similar finding that discovered with the HIV drug lopinavir that found the drug worked best when given earlier to less sick patients:
And as we’ll see in the following piece, that’s the same response Umer Raffat had following the disappointing preliminary findings of the China trial last week: Because those disappointing results were on a trial of severely ill patients we still don’t know how effective the drug is on moderately ill patients and that was the population Raffat is most interested in. And from a financial analyst’s standpoint you can understand why: there’s going to be WAY more moderately ill patients than severely ill patients so if remdesivir is found to be only effective for the moderately ill to ward off severe illness the inherent demand for the drug will skyrocket:
““For me, the real detail is NOT out yet: efficacy in patients that start early,” he said.”
It really is quite an important detail for anyone invested in Gilead: does it work on the much, much larger population of moderately ill patients? If so, and if the drug doesn’t actually work very well on the severely ill, the recommended use for remdesivir could be dramatically different, and more lucrative, than what was originally hoped for: instead of a drug to help save the severely ill, Gilead might have a drug that can at best stop the moderately ill from getting severely ill.
Of course, as we’ve seen, there’s no possible way for Gilead to ramp up the production of the drug enough to meet the global demand for the severely ill, let alone the much larger population of moderately ill patients. So the supply and demand balance could end up swinging even more in favor of Gilead’s investors, at least as long as an alternative drug for the severely ill patients isn’t discovered and run through clinical trials.
If remdesivir ends up being used on the moderately ill that’s also going to make the issue of side-effects much more important. It’s easier to justify side-effects for the severely ill. So it’s also going to be interesting to see what information about side-effects gets released by these trials. Other than the side-effect of massive profits for Gilead investors.
So as we can see, the primary good news currently available to us regarding the clinical efficacy of remdesivir is that there’s still some ongoing trials that might actually yield conclusion results in the future.
Now that remdesivir is officially humanity’s best hope for a drug to treat COVID cases according to the US government — despite the very mixed results from multiple clinical trials at this point — the question of just how much Gilead is going to charge for the drug is becoming much more urgent. And based on the following article, that’s a question without an obvious answer. Because while we’re hearing from the non-profit group Public Citizen is calling for Gilead to price remdesivir at $1, noting studies that say the drug can be made for only $0.93 per day, Wall Street analysts unsurprisingly have a very different set of price recommendation. The Institute for Clinical and Economic Review — a non-profit heavily funded by the drug makers, health insurance companies, and conservative mega-donors — suggested the drug should cost about $4,500. At least that’s what they suggested assuming further clinical data doesn’t show that it prevents or reduce deaths, which case the group says it should cost $390. Bernstein Research analyst Ronny Gal estimated that Gilead could price the treatment at about $5,000 and SunTrust analyst Robyn Karnauskas said Gilead could charge $10,000! That’s presumably $10,000 for a 10 day dose.
So will we see prices for a 10-day treatment closer to $10 or $10,000? That is yet to be determined, but it sure sounds like it’s going to be legally possible for Gilead to $10,000 for a round of treatment:
“It’s not clear exactly how much the drug will cost. For context, one non-profit that evaluates drug costs says it costs about $9.32 to manufacture a 10-day course of remdesivir treatment for one patient. Calculating the cost of development and trials, the Institute for Clinical and Economic Review says Gilead could charge as little as $390 for the drug. But Wall Street analysts are on an entirely different page, suggesting a price between $5,000 to $10,000, leading to billions in profits.”
Non-profits that care about public health want the drug as cheap as possible and Wall Street wants it as expensive as possible. It’s one of those frequent moments that should trigger questions about why on earth the mandate of profit-maximization is built into the fabric of how society functions but that’s where we are in the US. And that just might mean remdesivir is unaffordable to large numbers of people:
Also keep in mind that with all of the difficulties Gilead is going to run into when trying to scale up its production of remdesivir to deal with global demand, that means we should expect there to be a supply shortage whether or not the drug is $10 or $10,000 for a treatment. So there really could be a supply/demand situation early on that helps to increase the cost of drug. It could be effectively limited to the wealthy in 2020 until Gilead gets its supply chain up and running.
But would Gilead be that crass in the middle of global pandemic? Well, based on the vagueness of their public plans so far the answer appears to be a sold ‘maybe, they are thinking about it’. The company donated the initial supply of 1.5 million doses but that supply is expected to run out by late June if note earlier. That means Gilead could be directly making money for the sale of the drug in about a month. In addition, the company notoriously requested “orphan” status for remdesivir as the pandemic was breaking out...a move the company would only have done if it was planning on charging extra high prices for an extra long period of time. All of that, combined with Gilead’s record spending on lobbying this year, points in the direction of the company trying to figure out how it can charge as much as possible without provoking too much public backlash:
And don’t forget that Gilead didn’t simply request “orphan” status for the drug. The FDA granted that “orphan” status in late March. Gilead didn’t rescind its orphan status request until after the public outcry following that FDA approval:
“To qualify for an orphan designation, drug companies must show that their product will treat a population of fewer than 200,000 patients or that it would be unprofitable.”
The patient population has to be under 200,000. That’s one of the core rules for granting a drug “orphan” status. It’s not a bad concept as a program that encourages companies to develop drugs that have a relatively small market. But that’s a very different situation than requesting orphan status at the beginning of a global pandemic when case numbers are low but rapidly growing. And yet that’s exactly what Gilead did in an ultra-cynical move and the FDA rewarded them:
And note how HHS secretary Alex Azar, himself a former pharmaceutical lobbyist, refused to pledge to ensure approved COVID treatments are affordable during a congressional hearing in late February. So we’re seeing a constellation of moves by the Trump administration indicating that profitability, not affordability, is going to be the priority for the administration too:
And, again, it was only after the FDA made that egregious orphan status decision and the public outcry that followed that Gilead rescinded its orphan status request. It was too shameful even for Gilead (although not too shameful for the Trump administration, apparently). Still, apart for rescinding that request, all other signs are pointing towards Gilead being intent on making as much as it feels it can get away with. Public outrage is really the only thing stopping them for charging as much as possible. Fortunately the company’s schemes are inherently outrageous so there should hopefully be much more public outrage if Gilead decides to set prices closer to the $10,000 end of the price spectrum than $10. But that’s the line the company is going to be walking: how much can it charge without sparking an level of public outrage the company finds unacceptable. Which seems like the kind of situation that the public should find unacceptable and outrageous.
At the same time, we’re now hearing that Gilead is in talks with other drug manufacturers to produce the drug for other parts of the world. So that might help address the severe supply crunch somewhat but we’re still likely looking at a situation where there’s a sever supply crunch for the foreseeable future. That’s WHY Gilead is engaged in these talks. And even Beximco — an Bangladesch drug maker in talks with Gilead — is suggesting the cost could still be between $295 to $781 per patient in Bangladesh, which is effectively unaffordable for that country. It’s also the kind of arrangement that could shield Gilead from charges that it priced the developing world out of access to the drug and make it easier for the company to charge much more in the US and price poor Americans out of the drug:
“Beximco said a course of remdesivir treatment could cost between $295 and $781 per patient in Bangladesh.”
How many people in Bangladesh — A country with a per capita annual income of $602 in 2016 — are going to be able to afford $295 to $781 for a course of treatments? We just might find out. And that’s the relatively cheap cost that will presumably be much less than what Gilead will be charging in countries like the US. All in all, it’s a pretty awful situation surrounding what is seen as the best hope for medically address this disease in the short-run.
Then again, given that remdesivir doesn’t actually appear to be the wonder drug we were hoping for in treating COVID it’s possible this will all be moot because the drug is a total bust. Which would be a different kind of awful situation.
Here’s a set of articles related to the story of remdesivir and how it became ‘The’ drug that was almost exclusively pushed by the Trump administration as the top candidate for treating severe COVID-19 cases despite all the early indications that should have tempered expectations:
First, here’s a State News article the clinical trial of remdesivir run by the National Institute of Allergy and Infectious Diseases (NIAID) that goes into the internal deliberations made on the decision to change the study after the study had already started and then cut it short. Recall how it was the NIAID study that found that remdesivir cut the days to recovery from 15 down to 11 days but didn’t find a statistically significant difference in the mortality rates and based on those results the FDA an “emergency use authorization” for remdesivir.
The article describes now, initially, the NIAID study was design to test whether or not remdesivir could save lives (mortality rates). Patients would received remdesivir or a placebo and after 15 days their status would be assessed on a 1 to 8 scale. But as the results from another remdesivir clinical trial in China started trickling in, the NIAID researchers became concerned that their study design of only looking at the patient status on day 15 wouldn’t be able to show remdesivir was effective even if it really was effective (recall that the Chinese clinical trial found no statistically significant benefit to remdesivir in terms of mortality). In light this preliminary information, they made the decision in late March — when only 77 people were enrolled in the NIAID study — to change the study design to instead measure how long it took for patients to reach a threshold level of improvement and compare the times to improvement between the remdesivir and placebo group. So they essentially modified the study to make it easier to find some sort of positive result for remdesivir based on the preliminary data they were seeing from studies in China.
This decision to change the study design also ended up changing the number of people required to find a statistically significant result. OF the 1000+ patients ultimately enrolled in the study, they only needed to wait for 400 of them to achieve that “improved” status to answer the question they were answer. So the redesigned study proceeded along through April until the independent data and safety monitoring board (DSMB) met and made the recommendation that the second phase of the study — comparing a group getting remdesivir to a group getting remdesivir + Eli Lilly’s arthritis drug Olumiant — didn’t require a placebo. That decision prompted the researchers to take the people who had been receiving the placebo in the first phase of the trial and instead put them on remdesivir.
It was this decision to take the placebo patients off of the placebo in phase I of the trial that limited the ability for the researchers to ultimately make a statistically significant conclusion on whether or not remdesivir helps reduce mortality. As the following article describes, it was a pretty controversial decision, with a number of observers suggesting they really should have stuck with the ongoing placebo cohort in order to gather enough data to make a call on mortality. As some pointed out, there was indeed a nearly statistically significant result showing remdesivir help within mortality so if they had just stuck with the study a while longer that could have been achieved. The researchers carrying out the study counter that the results were basically close enough to demonstrate remdesivir helps patients and so withholding access to the remdesivir from the placebo group just to get a small about a statistical boost wasn’t worth it in terms of the potential costs to lives.
As the article makes clear, there is no obvious answer on whether or not they should have stuck with the placebo trial to get a statistically significant result and all of those interviewed agree it was difficult decision either way. But at the very end of the article, Ethan Weiss, a cardiologist at the University of California, San Francisco, makes perhaps the most relevant point about this debate: the fact that there are A LOT more clinical trials going on right now to test all sorts of different drugs is the real failing here. It’s not really controversial that these difficult decisions had to be made in this remdesivir clinical trial given twin needs to treat deathly ill patients while finding answers to questions about which treatments work. The problem is the infrastructure doesn’t exist to conduct a lot more studies like this during an emerging pandemic. As Weiss puts it, “We’ve squandered an incredible opportunity to do good science. If we could ever go back and do something all over, it would be the infrastructure to actually learn something. Because we’re not learning enough.”
And that critique again leads us to the question of why remdesivir has been almost exclusively focused in on in the quest for COVID drugs. Why has there been almost no meaningful interest in the early reports of remarkable results from “Thai cocktail” or OyaGen’s Oya1 compound while almost all of the attention has been on remdesivir, a drug that’s difficult to manufacture and can only be administered in a hospital setting? Those are the kinds of questions that need to be asked in the context of the broader challenge of setting up a greater capacity for clinical trials.
Now, as we’re going to see in the second and third article excerpts below, it turns out a group of billionaires and venture capitalists have been basically designing the White House’s approach to leading the efforts to finding a covid drug therapy and just so happens that the groups has been promoting remdesivir. The group is calling itself “Scientists to Stop COVID-19,” and describes itself as an “ad hoc review board” for the torrent of coronavirus research, “weeding out” flawed data before it reaches policymakers. The group has ties to Peter Thiel and other Trump administration figures and is also reportedly acting as a go-between for pharmaceutical companies seeking to build a communication channel with Trump administration officials. Recall how Thiel’s Palantir has already been given major federal contracts for handling the data aggregation and analysis for tracking the pandemic. So there’s an informal group of billionaires with pharmaceutical company ties that appears to be shaping the Trump administration’s efforts to find a drug therapy and this group has apparently been pushing remdesivir quite a bit.
As we’re going to see, the group set of recommendations were almost singularly focused on remdesivir. You can see it’s 17-page set of recommendations here. Look at the “First Wave: Repurposed drugs” part of the document. It’s almost ALL about remdesivir. The group is so pro-remdesivir that it even mention how the group is now recommending remdesivir be given in an early stage of the infection, the kind of move that makes the drug effectively worthless because almost EVERYONE will need to be put on remdesivir for that therapy approach to work. Giving it early on in an infection might be appropriate for people in very high risk groups (e.g. people with compromised immune systems), but it would have to be limited to those patients for the supply to be remotely adequate. It’s basically looking for an excuse to use remdisivir after the initial high hopes for the drug fizzled.
So overall it sounds like one of the big questions facing the world in terms of how to deal with future novel viral outbreaks is the question of what needs to be done in advance of that outbreak to ensure there’s the available capacity for large numbers of parallel clinical trials. But that’s a question for future outbreaks. It’s too late to do that in this outbreak. We’ve already wasted that precious time in setting up the infrastructure for carrying out more clinical trials. So for this outbreak the more relevant question is whether or not the billionaire-backed “Scientists to Stop COVID-19” is using its influence with the Trump administration to ensure only their favored drugs get the favored treatment when prioritizing which drug are tapped for those limited trials.
Ok, here’s that Stat News article on internal deliberations behind the decisions to modify the NIAID study design and then cut it short before the question of remdesivir’s impact on mortality could actually be answered:
“The National Institute of Allergy and Infectious Diseases has described to STAT in new detail how it made its fateful decision: to start giving remdesivir to patients who had been assigned to receive a placebo in the study, essentially limiting researchers’ ability to collect more data about whether the drug saves lives — something the study, called ACTT‑1, suggests but does not prove. In the trial, 8% of the participants given remdesivir died, compared with 11.6% of the placebo group, a difference that was not statistically significant. ”
One thing we can say for sure about the decision to end the placebo part of the trial and give placebo patients remdesivir is that it couldn’t have been an easy decision. It was a decision of whether or not to let the people on placebos get the drug after there was statistically insignificant (but nearly significant evidence) that the drug helps. Do they withhold treatments in order to prove the treatment helps if they already strongly suspect it helps? That’s the question they faced and the NIAID decided to grant the placebo cohort the treatment and leave the question of whether or not remdesivir helps with mortality an open question:
Note that next phase of the trial, comparing remdesivir to remdesivir + Olumiant, is just getting underway now.
But it’s Ethan Weiss who makes perhaps the most important point regarding the debates over these remdesivir study designs: it’s insane that there aren’t more clinical trials going on right now for more drug therapies:
Civilization basically put all of its drug ‘eggs’ in the remdesivir ‘basket’. That’s why the debates over these studies are so important...because we haven’t really been aggressively looking into other drugs simultaneously like we should have. So why is that? Is it a lack of physical infrastructure or is it a lack of organization? Those are important questions to answer going forward regarding future epidemics. But for this one, a bigger looming question is what on earth is the agenda of “Scientists to Stop COVID-19” because it sure sounds like this is the group that’s shaping the US’s federal policy on seeking out drug therapies. And while the group claims to have no financial interests in mind for their efforts, that’s a little hard to believe when you look at who is behind:
“Calling themselves “Scientists to Stop COVID-19,” the collection of top researchers, billionaires and industry captains will act as an “ad hoc review board” for the torrent of coronavirus research, “weeding out” flawed data before it reaches policymakers, the Wall Street Journal reported on Monday.”
An “ad hoc review board” that will be “weeding out” flawed data before it reaches policy makers. So this private group has basically assumed the role of data-gatekeeper for the Trump White House. Now, if this was just a group of scientists that would be one thing, but this is a group led by a venture capitalists with ties to figures like Peter Thiel of billionaire and is acting as a go-between for pharmaceutical companies. That’s the group that’s “weeding out” flawed data before it reaches policymakers:
And note how the group compiled a 17-page plan on developing therapies that includes promoting remdesivir:
So is Gilead one of the pharmaceutical companies that’s been working with this group?
Now, it’s unclear from that report just how much emphasis this group has been placing on remdesivir as opposed to other drugs. But based on the following article, it sounds like the group recommended the US federal government work with Gilead to expedite clinical trials on remdesivir and is now recommending the drug be used at an early stage of the infection. Again, don’t forget that the recommendations that remdesivir be given at an early stage of the infection is basically fallback position after the drug has failed to show a strong effect on severely ill patients, but it’s a fallback position that could cause demand for remdesivir to spike and make Gilead a lot more money. So, again, we have to ask: has the federal governments extreme focus on remdesivir been shaped, in part, by the influence of “Scientists to Stop COVID-19”?:
“Government entities and agencies appear to adhere to the recommendations outlined by the group, with the Journal reporting that the FDA and the Department of Veterans Affairs (VA) have implemented some of the suggestions, namely relaxing drug manufacturer regulations and requirements for potential coronavirus treatment drugs.”
Government entities and agencies appear to adhere to the recommendations outlined by the group. That’s what we’re seeing. So whether or not the group formally has authority to make these decisions, it appears to have informal authority. And it’s been using that informal authority to recommend exactly what we’ve seen: the US federal government working with Gilead to expedite the clinical trials of remdesivir. And now the group is also recommending administering remdesivir to patients early on, a recommendation that’s tacit admission that the drug has modest benefits at best but they’re continuing to push it anyway:
And notice what we aren’t hearing in those recommendations: that the US federal government work with other companies to expedite the clinical trials of other drugs. And it turns out if you look at that 17-page list of recommendations, ALMOST THE ENTIRE SECTION ABOUT DEVELOPING DRUGS IS ABOUT REMDESIVIR. Yep. It briefly mentions a few other drugs and then has three pages talking about remdesivir. That document is available for download here: Look at the “First Wave: RERPURPOSED DRUGS” section on Pages 5–7. Virtually the entire section is dedicated to promoting remdesivir. So it sure sounds like this group of billionaires and venture capitalists (with a few legit scientists thrown in) has been one of the groups promoting this almost singular federal focus on remdesivir.
So when it comes to the question of how to ensure the US has adequate capacity for large-scale clinical testing of new drugs in the face of an emerging pandemic, it’s going to be important to keep in mind that secretive groups of billionaires pushing their pet agendas is one of the issues that’s going to have to be addressed.
And in other covid clinical trial news...
Following up on the Scientists to Stop Covid-19 group of billionaires and venture capitalists (which some actual scientists thrown in for good measure) who appear to be calling the shots on the Trump administration’s COVID drug development strategy, it’s worth noting a rather significant point about the figure said to be behind the formation of this group: Dr. Tom Cahill.
As we saw, Dr. Cahill’s connections in Silicon Valley include Peter Thiel. And as we’ve also seen, Thiel’s Palantir has emerged as a central entity in formulating the tracking the White House’s coronavirus response. Also recall how Trump turned to Thiel back in December of 2016 during the transition period to help fill a number of important positions involved health and science, with Thiel reportedly being focused on the FDA, NIH, Health and Human Services, and the Office of Science and Technology Policy. So Trump has been turning to Thiel for matters involving science and public health from the very beginning of his administration, which makes it a good bet that Trump once again turned to Thiel for advice on how to handle this pandemic.
Here’s the very interesting part involving Dr. Cahill and Thiel: it sounds like Dr. Cahill basically owes his career to Thiel. Or rather, the network of investors around Thiel. Because as we’ll see in the following article, the 33-year-old Cahill graduated from Duke University with his MD and PhD just two years ago. He got a job at the investment firm Raptor Group and then went on to start his venture capital firm Newpath Partners. It was just last year that Newpath raised its initial $125 million on funding which came from a small group of investors including Thiel. That’s basically a description of Thiel’s investor network setting up Newpath Partners which strongly implies Cahill owes his current wealth and career as a venture capitalist to Thiel.
So the guy who is apparently the driving force behind this outside group of advisors that has taken the lead on the White House’s drug development response is basically a vassal of Thiel and the other early investors in Newpath.
As the following article notes, another initial investor in Newpath was venture capitalist Brian Sheth, who arranged for the group to contact the White House via his connections to Republican National Committee chairman Tommy Hicks, Jr. As we’ve seen, Hicks isn’t just the head of the RNC. He’s also hunting buddies with Donald Trump, Jr. and a friend of J. Kyle Bass and brought Bass into the White House to formulate the Trump administration’s policies regarding China (a policy that would be wildly profitable for Bass if it ended up tanking the Chinese economy).
Yes, two key financial backers of Cahill’s Newpath, Thiel and Sheth, both had deep ties to the Trump administration. And, lo and behold, it’s Cahill who emerges at the official ring-leader for this ‘private’ group of COVID advisors that has apparently been determining the federal governments COVID response policies. Don’t forget what we’re told about the influence of this group on the White House: it’s acting as an ad hoc advisory board that “weeds out” data before it reaches policy-makers and government agencies appear to have adhered to their recommendations. In other words, they might technically just be giving “advice” to the Trump administration but federal agencies appear to be treated that advice as orders.
So we have to ask: did the White House request that someone set up this group? Was a ostensibly third-party group giving advice seen as a means of allowing the White House to get the ‘outside advice’ it already desired? Perhaps as a means of deflecting blame if the advice ends up backfiring? It’s an intriguing possibility because we know the White House has turned to Thiel’s Palantir and has likely been coordinating extensively with the RNC via Hicks. And both Thiel and Hicks’s friend Sheth basically helped create the career of Dr. Cahill just last year. Were they the actual figures behind the formation of Scientists to Stop Covid-19, setting up Cahill as the official face for the group?
“At the helm of the effort: The 33-year-old and very-much-under-the-radar venture capitalist Tom Cahill, who leads life sciences-focused Newpath Partners. Cahill completed his M.D. and PhD at Duke University a mere two years ago before landing at blue-chip investment firm Raptor Group through a friend. He went on to found Newpath with some $125 million after impressing well-connected names like venture capitalist Peter Thiel and Vista Equity Partners co-founder Brian Sheth.”
From graduate student to venture capitalist guiding the White House’s pandemic response in just two years. Tom Cahill is quite the high-flyer. Thanks largely to the ~$125 million in capital used to create Cahill’s Newpath Partners just last year. And the small group of investors in Newpath just happens to include Peter Thiel and Brian Sheth, a good friend of RNC chairman Tommy Hicks Jr.:
So who really assembled this initiative? Well, according to the following Strait Times article describing how the group originally formed, we’re told that Cahill was getting peppered with questions from Newpath’s investors in early March about the virus so he organized a conference call to shared some ideas with them. He apparently expected about 20 people on the call, but when it actually happened he discovered there were hundreds of people on the call, including advisors to Vice President Mike Pence. So Pence’s advisors were involved with this group before it was even a formal group:
“In early March, as the coronavirus death toll mounted, Dr Cahill’s investors peppered him with questions about the virus and he organised a conference call to share some against-the-grain ideas on how to accelerate drug development, among other things.”
It was supposed to just be an innocent conference call to 20 or so Newpath investors. Investors that would obviously include Thiel and Sheth. But then Cahill discovers hundreds of people on the call, including advisors to the Vice President:
So the White House was clearly interested in this group before it even formed. And yet the way this group is portray itself to the media, it’s just a bunch of concerned scientists who are giving their unfiltered advice. And note this strange anecdote we keep seeing in reports about this group: it was Mr Steve Pagliuca, one of Newpath’s investors, who passed the report to Treasury Secretary Steve Mnuchin:
An aide to the Vice President was literally on the call and yet somehow Steve Mnuchin is the one who receives the report?! It’s the kind of detail about this group that has the feel of being intentionally put out there to make it seem like the group really was independent of the White House and had to jump through hoops to make the White House know about its recommendations.
So it’s looking more and more like this group that has emerged as a key decision-maker in the Trump administration’s COVID response was set up either at the behest of the White House or at least with the close cooperation of the White House and that extremely close relationship is something they would prefer the public not recognize. Why is that? It’s an important question that’s going to be increasingly important the more the Trump administration’s COVID response continues to flail, along with the related grim question of who might be profiting from all that flailing.
Here’s a pair of articles worth keeping in mind regarding remdesivir, the focus that’s been put on that drug as humanity’s best therapeutic hope for a covid treatment despite all of the obvious problems with that strategy, and the apparent influence of the “Scientists to Stop COVID-19” industry-backed group in pushing remdesivir:
There was a notable departure from the White House late last month. Notable in part because of who it was and also somewhat notable for the timing. Recall how we had that mix of good-ish/bad-ish news from two remdesivir clinical trials on the same day and in response the FDA immediately authorized remdesivir for emergency use. Well, on that same day we had the announcement that long-time Gilead lobbyist Joe Grogan was leaving his position as the head of the White House Domestic Policy Council. So at a minimum it was interesting timing, especially since he was part of the original coronavirus task force the Trump administration formed in January.
Grogan’s departure from the White House reportedly expected for some time so it’s unclear if Grogan’s decision to choose that day to announce his departure has has anything to do with the White House’s treatment of remdesivir but the fact that he announced his departure on the same day the FDA granted the drug emergency use status following some rather disappointing clinical trial results at least hints at some possible sensitivity to the political optics of the situation.
And as we’ll see in the second article below, one of Grogan’s specialties in the White House appears to be a greater political sensitivity to bad optics. Specifically, greater sensitivity to bad optics than Health and Human Services (HHS) Secretary Alex Azar. That’s the picture that emerges when we hear about a policy battle between Grogan and Azar that pits Grogans as the voice of relative reason compared to Azar when it come to shilling for the pharmaceutical industry. The fight was over dueling plan to address high drug prices and Azar was pushing a plan that was such a massive giveaway to the pharmaceutical industry Grogan had to step in. Azar’s plan was to pass a regulation that would ban the practice of having drug manufacturers pay rebates to insurers. Yes, the plan for controlling rising drug prices was seriously to ban discounts drug manufacturers offered to insurers, a plan that likely would have led to a rise in premiums. It turns out this was the ‘fix’ to drug prices the drug manufacturers had been aggressively lobbying for and Alex Azar, the former pharmaceutical lobbyist and executive, was all in favor or it. Surprise!
What was actually somewhat surprising was that it was Grogan, another former pharmaceutical lobbyist, who had to step in and block the plan. That’s how bad it would have looked to ‘fix’ high drug prices by blocking drug discounts. Grogan instead advocated for a drug control plan that involved tying prices for US consumers to international prices which surprised many because that’s a solution generally not favored by Republicans. It was spun as one of those examples when Trump and his team might be willing to be more ‘populist’ than past Republicans, so of course the plan was only talked about and was never actually implemented.
So Grogan’s big legacy at the White House was blocking bill intended to lower drug prices that would have saved drug manufacturers billions and probably raised drug prices. It’s not the greatest legacy but it could be worse. It could be Alex Azar’s legacy, which is still being built.
Ok, here’s a piece about the announcement of Grogan’s departure. The departure was announced in the Wall Street Journal on the morning of Wednesday, February 29, the same day we got our first public reports of the NIAID clinical trial of remdesivir that was positive enough to show it shortened the time to recovery and the same day the FDA granted remdesivir emergency use status:
“Grogan was one of the original members of the White House coronavirus task force launched in late January. It was not immediately clear who would replace him as head of the Domestic Policy Council.”
The Gilead lobbyist who went on to assume a power role shaping White House policy also happened to be one of the original coronavirus task force members. Might that have had something to do with the disproportionate focus placed on Gilead’s remdesivir from the beginning of the pandemic? And did the so-so reports of remdesivir’s effectiveness against COVID in the NIAID study have something to do with Grogan’s decision to leave on the same day? Who knows but the timing was certainly interesting. And sadly, as the following article describes, while having a former Gilead lobbyist crafting policy is obviously problematic, Grogan’s legacy was defined by being not as big a shill as Alex Azar (who is still HHS Secretary and still shaping the federal coronavirus response):
“The Trump administration has only rewarded Grogan’s unruliness: In a remarkable two-year span, he has vaulted from lobbyist for the pharmaceutical giant Gilead Sciences to White House budget adviser to director of the president’s Domestic Policy Council. Grogan’s chaotic ascent to the White House’s highest ranks, described to STAT in interviews with eight current and former Trump administration health officials and an array of conservative lobbyists, is defined more by feud than by policy triumph — and on drug pricing in particular, his track record consists more of blocking others’ policies than advancing new ones.”
He may not have received much attention, but Joe Grogan quietly became one of the most influential figures in the Trump administration. Despite Trump’s pledge to not hire a bunch of lobbyist:
And much of that time in the Trump White House was apparently spent fighting with Alex Azar, another former lobbyist, to block policies that were so egregiously designed to benefit the drug industry that Grogan it would end up backfiring. Policies like lower drug prices by blocking drug discounts to insurers. Or allowing insurers to drop coverage or drugs for mental health or rare disorders if the prices rose faster than inflation. Azar was all in favor of those policies and Grogan had enough sense to realize that they would look horrific if implemented. That was the status of the drug policy-making insider the Trump administration: the battle of the shills between the sane shill and the insane shill:
As we can see, Grogan won many these policy battles in in the end but he didn’t win any fights for actually better policies. He just helped avoid much, much worse policies that would look so bad they provoke a backlash. And now he is leaving while his policy foe, Azar, remains in place, at least for now.
So as the world continues to search for some sort of covid drug therapy as soon as possible, it’s worth noting that one of the top drug industry shill’s inside the Trump administration is leaving very soon leaving and his departure is probably going to allow the remaining drug industry shill, Alex Azar, to become an even bigger shill. That’s how big the White House’s industry-shill problems are: A major pharm-shill leaves and somehow that made the White House’s shill problem even bigger.