Ratio Scientiae
RATIO SCIENTIAE BLOG
  • Home
  • Meet the Author
  • Ratio Scientiae Blog
  • Random Science
  • Writing & News
  • Nonfiction Books
    • Science Can Be Right Because It Can Be Wrong
    • The Gift of Science
    • Random Science
  • Fiction Books
    • The Sun Zebra
    • Spirit Women
  • Science Cat (Mascot)
  • Contact

8/8/2020

Cultured Cells, Dr. Fauci, and a Bold Hypothesis to Explain Why Hydroxychloroquine Alone Doesn't Work for COVID-19

4 Comments

Read Now
 
How did the notion arise that hydroxychloroquine could be used against the SARS-CoV-2 virus that causes COVID-19? I want to spend some time on this because it involves an article that is often quoted to slander Dr. Fauci.
​

PictureVero E6 Cells in Culture and Hydroxychloroquine
In 2005 there was a study where chloroquine (a drug related to hydroxychloroquine) was found to be effective at reducing infection with the virus, SARS-CoV (which is 79% related to the COVID-19 virus, SARS-Cov-2), in primate cells in culture. Early on in the COVID-19 pandemic, it was claimed that Dr. Fauci was lying when he said that there was no good evidence for the effectiveness of hydroxychloroquine against COVID-19 because he has known about this article for 15 years. This claim is still being made over and over in social media, and has even been retweeted by some high profile people in the hydroxychloroquine debate.

Any scientist who has worked with cells in culture (for example, me) will tell you that extrapolating from cultured cells to the full organism is fraught with peril. The metabolism of cells in culture and the way they react to chemicals or biologicals can be substantially different from the way they react as part of the full organism. In the full organism, cells are in a three dimensional matrix, interacting with other cells types and exposed to the daily cycles of fluctuations in levels of nutrients, hormones, temperature, oxygen, etc. Also, any drugs delivered to the organism, depending on the mode of delivery, may have to pass through several layers of other cells before they reach their intended target. In culture, the cells are in a two dimensional environment interacting only with cells like themselves under fixed conditions. When you deliver a drug to the cells in culture, it reaches them right away. So, more often than not, what you get using cell culture, is different from what you get in the full organism.

Additionally, the cells used in the study mentioned above were Vero E6 cells. This is a cell line derived from the kidney of an African Green Monkey, and these cells even have a different number of chromosomes compared to those of the original monkey. Infecting cultured cells from the kidney (not the airways) of a monkey (that are different from human cells and even from the cells of the original monkey) with the SARS-Cov virus (which is different from the COVID-19 virus), treating them with chloroquine (which is different from hydroxychloroquine), and then extrapolating the results to the full human being to argue that Dr. Fauci “…has known for 15 years that chloroquine and it’s even milder derivative hydroxychloroquine (HCQ) will not only treat a current case of coronavirus (“therapeutic”) but prevent future cases (“prophylactic”).” is scientifically inaccurate, to say the least.
 
Then why do scientists use these monkey cells to test compounds against viruses that infect humans? The answer is that these cells can be infected with many viruses and they are a convenient, but very preliminary, test that can be used to screen many compounds quickly, and identify those that display activity against viruses. Once a compound is identified, it is subjected to more complex tests that may involve human cells and studies with whole animals to see if it still works. As it turns out, hydroxychloroquine has been recently been tested with these Vero E6 cells, and it has been found to have antiviral activity against the SARS-CoV-2 virus. But can hydroxychloroquine stop the COVID-19 virus from infecting cells from the human airway, which is the main site of entry of the virus into the body?
 
A study performed with reconstituted airway epithelium developed from primary human nasal or bronchial cells indicated that hydroxychloroquine had no activity against the COVID-19 virus. Why would this be the case? A group of researchers have proposssed a very clever answer to this question.
 
There are two ways that the COVID-19 virus can get into a cell. One involves the uptake of the virus into an intracellular compartment called the “endosome”. The endosome is a compartment that is acidic which is optimal for the functioning of an enzyme called Cathepsin L (CatL) that acts on the virus and activates it. One of the effects of hydroxychloroquine is to lower the acidity of the endosome which impairs the activity of CatL and thus hinders the activation of the virus. However, the cells of the human airway epithelium have low levels of CatL. In these cells, the entrance of the virus is achieved through a second route involving activation by an enzyme called TMPRSS2 which is not dependent of endosomes or acidity and is therefore not affected by hydroxychloroquine. Thus the CatL (hydroxychloroquine sensitive) pathway is predominant in Vero E6 cells, whereas the TMPRSS2 (hydroxychloroquine insensitive) pathway is predominant in the human lung cells. If you use Vero E6 cells that have been genetically engineered to express the TMPRSS2 enzyme (and thus have the TMPRSS2 pathway too), then hydroxychloroquine loses its ability to inhibit the COVID-19 virus infection of the cells! Other researchers have also found that the inhibition of SARS-CoV-2 entry into cells by hydroxychloroquine is antagonized by the presence of the TMPRSS2 pathway.
 
The above is a bold hypothesis that explains why hydroxychloroquine alone has not been found to work in the best-designed studies (1, 2, 3, 4, 5, 6, 7) performed so far. The reasoning is that it does not work because it doesn’t affect the TMPRSS2 pathway of COVID-19 virus activation that is the predominant viral activation pathway in human airway cells! This hypothesis also eliminates the original rationale to use hydroxychloroquine, which arose from using Vero E6 cells as a screen, and it shows how wise Dr. Fauci was in not giving a lot of importance to that very preliminary 2005 study.
 
Nevertheless, notice I mentioned that the above proposal is just a hypothesis. Some people have interpreted the results to mean that hydroxychloroquine reduces the COVID-19 viral infection in monkeys, not humans. However, hydroxychloroquine does not reduce or prevent COVID-19 infection in macaque monkeys. More studies are needed before we can conclude that this is the reason why hydroxychloroquine doesn’t work in humans.
 
However, if you are one of the people that argue that hydroxychloroquine by itself is not active (has no antiviral activity), but rather that it enhances the uptake of zinc which has the real antiviral action, then this hypothesis does not affect your claim. Whether zinc acts with hydroxychloroquine to ameliorate or prevent COVID-19 remains to be demonstrated in well-designed clinical trials (and several are ongoing). But what we can say right now is that the best evidence we have so far indicates that hydroxychloroquine IS NOT effective by itself or with antibiotics against COVID-19, and it’s time we started accepting this.

 
Micrograph of Vero Cells under green light (100X) by Y tambe is used here under an Attribution-Share Alike 3.0 Unported license. This micrograph was merged with an image of hydroxychloroquine by Fvasconcellos which is the public domain.

Share

4 Comments
Sid Belzberg
8/16/2020 06:14:24 pm

Why would you not use HEK293 cell line of human kidney cells? HCQ is not effective late stage when serious respiratory set in.
So since it works in vero cells would the next logical step would be HEK293 cell line. The idea is to stop covid early before viral infection spreads to lungs?

Reply
Rolando garcia
8/20/2020 04:27:10 pm

Thanks for your comment, Sid, but the main route of entry of COVID-19 into the body is through the epithelium of the airways (it gets to the kidneys later). Advocates for HCQ say it should be used very early or even before the virus infects the lungs (as a prophylactic). If the hypothesis I outlined above is true, then this will not work. If you want to model the later stages of the infection in organs such as the kidney, then a model like HEK-293 cells would be justified.

Reply
Robert Clark link
8/27/2020 07:45:44 am

That report showing HCQ not antiviral in human lung cells very misleading. It was done on *cancer* cells, with study on normal cells “pending”.
Why not just do it on normal cells to begin with?

See here:

https://twitter.com/richardursomd/status/1293950402191335431?s=21

Robert Clark

Reply
Rolando Garcia
8/28/2020 07:24:22 pm

Thanks for your comment, Robert. I provided a link to the article that did what you claimed should have been done ( https://www.nature.com/articles/s41586-020-2558-4 ), just download the PDF file to read it. A more up to date report is this one ( https://www.nature.com/articles/s41467-020-17907-w ). The evidence indicates that hydroxychloroquine does not have antiviral activity in human cells. I tried to go to the twitter account of the person you quote to set the record straight, but he blocked me a while ago.

Reply

Your comment will be posted after it is approved.


Leave a Reply.

Details

    Categories

    All
    911
    Absence Of Evidence
    Adrenaline
    Adrenochrome
    Advances In War Medicine
    Affidavits
    Airplane On Conveyor Belt
    Alder's Razor
    Alfred Wegener
    Alzheimer's Disease
    Amyloid Theory
    Ancient Astronauts
    Animal Rights
    Animals
    Anthony Fauci
    Anthropomorphism
    Antibodies
    Anti Vaccination
    Astronauts
    Authority Figure
    Autumn
    Bambi
    Believers
    Bias
    Big Bang Theory Sitcom
    Bigfoot
    Bill Ney
    Black Death
    Black Holes
    Blind Experimental Design
    Brain
    Brains
    Building 7
    Buoyancy
    Cancer
    Cannonballs
    Carnivores
    Catoctin Mountains
    Cell Culture
    Center Of Mass
    Challenger
    Chance
    Chemical Names
    Chemical Reactions
    Chemtrails
    Chesapeake Bay
    Child Abuse
    Child Testimonies
    Chimborazo
    Citations
    Citogenesis
    Civil War
    Climate Change
    Climategate
    Climate Skeptics
    Clinical Trial
    Coelacanth
    Coincidence
    Cold-Stress
    Communicating Science
    Completeness Of Scientific Theories
    Consciousness
    Conspiracy
    Contrails
    Controls
    Coquina Rock
    Coronavirus
    Counterintuitive Facts
    COVID19
    COVID 19 Vaccine
    COVID-19 Vaccine
    Creationism
    Cross-Sectional Method
    Cryptozoology
    Dan Shechtman
    Demonic Possession
    Density
    Devotion To Science
    Dihydrogen Monoxide
    Dinosaurs
    Discrimination
    Disgust
    Dishonesty In Science
    Diversity In Methodologies
    Diversity In Scientists
    DNA
    Doctors
    Dog Experiments
    Donald Trump
    Double Slit Experiment
    Do Your Own Research
    Dreams
    Dr. Gloom's Crypt Of Curiosities
    Drugs
    Dust Bunnies
    Eclipse
    Efrain Racker
    Einstein
    Elections 2020
    End Of The World
    Erosion
    Established Science
    Everest
    Evidence
    Evolution
    Exorcism
    Experimenter Bias
    Experiments You Can Do In Your Home
    Experts
    Extinction
    Face Masks
    Facts
    Faith
    Faith Healing
    Fall
    Falsifiability
    Fantastical Claims
    Fauna
    Fear
    Feynman
    Finger Snapping
    Fosbury Flop
    Francis Crick
    Frankenstein
    Fraud
    Frederick's Municipal Forest
    Free Will
    Friction
    Fruit Fly
    Funerals
    Funny
    Galaxies
    Genes
    Genius
    Geology
    Ghost
    Global Warming
    Global Warming Denial
    God
    Gravitational Lens
    Gravitational Waves
    Gravity
    Gun Violence
    Hanlon’s Razor
    Hearing
    Hearing Aids
    Hearing Loss
    HeLa Cells
    Henrietta Lacks
    Heroic Science
    Hitchens's Razor
    Hoax
    Homosexuality
    HPV Vaccine
    Human Experimentation
    Human Folly
    Hunting
    Hurricane
    Hydroxychloroquine
    Hypothesis
    Ignaz Semmelweis
    Ignorance As Evidence
    Immunotherapy
    Infamy Or Glory
    Influenza
    Insults
    Intelligence
    Intelligence Tests
    Intelligent Design
    Intersex
    Iraq War
    Irish Washerwoman
    Isaac Asimov
    James T. Kirk
    James Watson
    Katherine Hayhoe
    Language
    Lazarus Effect
    Left Fork Rocks
    Level Of Detail
    Libet Experiment
    Lightning
    Limericks
    Limitations Of Science
    Loch Ness Monster
    Lord Howe Island Stick Insect
    Loud Music
    Luck
    Mad Scientist
    Magnus Effect
    Malaria Vaccine
    Max Planck
    Medical Risks
    Medical Terms
    Mediums
    Men
    Mental Illness
    Mice
    Microbiome
    Milgram Experiment
    Mind
    Mind In The Gutter
    Misuse Of Science
    MMR Vaccine
    Mnemonic Devices
    Moments Of Discovery
    Monty Hall Puzzle
    Moon
    Movies
    NASA
    Natural
    Nature
    Nature Of Science
    Negative Evidence
    Nerds
    Newton
    Nobel Prize
    NOMA
    N-Rays
    Obesity
    Occam's Razor
    Open Mind
    Ouija Board
    Outreau
    Oxbow Lakes
    Para-Dimethylaminobenzaldehyde
    Paranormal
    Pasteur Louis
    Peak Of Illusion
    Peers
    Perception
    Philosophy
    Phobias
    Phrenology
    Physics
    Pink Lady's Slippers
    Plague
    Politicization Of Science
    Polywater
    Popper’s Falsifiability Principle
    Possible/Impossible
    Power To The People!
    Predatory Journals
    Pregnancy
    Premonitions
    Probability
    Propaganda
    Prophesy
    Pseudoscience
    Psychic
    Publication
    Puerperal Fever
    QAnon
    Quack
    Quackery
    Quantum Mechanics
    Quartzite
    Racism
    Radical New Ideas
    Radioactivity
    Radium
    Randomness
    Ratio Sapientiae
    Ratio Scientiae
    Reality
    Reason
    Religion
    Rock Climbing
    Rosalyn Franklin
    RSV Vaccine
    Sagan's Standard
    Salem Witch Trials
    Sample Size
    Science Fiction
    Science Jokes
    Science Pranks
    Scientific Consensus
    Scientific Establishment
    Scientific Guidelines
    Scientific Journals
    Scientific Method
    Scientific Names
    Scientific Question
    Scientific Terms
    Scientific Theories
    Seashells
    Self-Experimentation
    Shape Of The Earth
    Skepticism
    Skeptics
    Skin Color
    Slavery
    Snake Oil
    Soccer
    Sonic Hedgehog
    Space
    Spanish Flu
    Spontaneous Generation
    Stanley Prusiner
    Stars
    Star Trek
    Statistical Significance
    Statistics
    Sublime/Ridiculous
    Suicide
    Sun
    Superstition
    Surface To Volume Ratio
    Swanson Conversion
    Swine Flu
    Tangier Island
    Taxonomy
    Technical Details
    The Support Of God
    Thomas Young
    Timeline Method
    Tooth Worm
    Transposable Elements
    Trusted Messenger
    Trust In Scientists
    Truth
    Tyranny Of Fantasy
    Understanding
    Universe
    Vaccine Hesitancy
    Vaccines
    Vacuum
    VAERS
    Valley Of Despair
    Values
    Video Games
    West Side Story
    West Virginia Penitentiary
    Wikipedia
    William Shatner
    Wolf Rock
    Women
    World Trade Center
    Xenophobia
    Y Chromosome
    Zinc
    Zombies

    Archives

    October 2024
    September 2024
    August 2024
    July 2024
    June 2024
    May 2024
    April 2024
    December 2023
    November 2023
    October 2023
    September 2023
    May 2023
    April 2023
    March 2023
    February 2023
    January 2023
    November 2022
    October 2022
    September 2022
    August 2022
    July 2022
    June 2022
    May 2022
    April 2022
    August 2021
    July 2021
    June 2021
    May 2021
    April 2021
    March 2021
    February 2021
    January 2021
    November 2020
    October 2020
    September 2020
    August 2020
    July 2020
    June 2020
    May 2020
    April 2020
    March 2020
    February 2020
    January 2020
    November 2019
    October 2019
    September 2019
    August 2019
    July 2019
    June 2019
    May 2019
    April 2019
    March 2019
    February 2019
    January 2019
    December 2018
    November 2018
    October 2018
    September 2018
    August 2018
    July 2018
    June 2018
    May 2018
    April 2018
    March 2018
    February 2018
    January 2018
    December 2017
    November 2017
    October 2017
    September 2017
    August 2017
    July 2017
    May 2017
    April 2017

    RSS Feed

Proudly powered by Weebly
  • Home
  • Meet the Author
  • Ratio Scientiae Blog
  • Random Science
  • Writing & News
  • Nonfiction Books
    • Science Can Be Right Because It Can Be Wrong
    • The Gift of Science
    • Random Science
  • Fiction Books
    • The Sun Zebra
    • Spirit Women
  • Science Cat (Mascot)
  • Contact