It’s as simple as 1,2,3,4: You make them audit each other.

Do something like we did:

  1. Create an UNLISTED video on YouTube. Don’t share the link to anyone.
  2. Make a PRIVATE blog post with the video (and not much else to attract people) on another platform, one with detailed and credible traffic reports like WordPress preferably live traffic reports similar to YouTube’s. Set it private so that no one can find the link unless you give it to them. And DON’T share the link with anyone, except… see below
  3. Make a PUBLIC Facebook post with the PRIVATE blog link. Now the only access gate to the blog post and the video is Facebook. Boost the post immediately, even if only for 5-10 bucks, it’s enough to generate good comprehensive statistics from Facebook. Make sure there’s no other links or distractions included so the audience can’t go anywhere else or come from anyone else, that compromises the experiment
  4. Compare the Facebook reports with the ones from the blogging platform and the one from Youtube.
    If they are honest, the numbers vary only about 5-10%.
    If you have my luck, Facebook reports 2-300% more than the blog, while YouTube has capped your numbers and deletes views same way Dominion deleted Trump votes, so it has no relation whatsoever with the other two.
    That’s the case for the Fauci Fashion song below, which has not been allowed to cross 9k for over half a year, despite some intense promo efforts.

5. (Optional): Feel free to add more elements to the scheme, the only rule is to be able to accurately monitor the traffic, numbers as well and sources, destinations, gates etc. This model is in 3D, but any number can go if you extrapolate the method intelligently.

IMPORTANT: As time passes, if people start sharing the links organically, they can create distortions and interferences in your controlled audience funnel, first 2-3 days are the most accurate, from there things can go either way. Nevertheless, that can’t explain my numbers either, but can explain smaller deviations from the general rule.

If you think a whole industry went away with Cambridge Analytica, I lol

This post is an upgrade of an earlier post focused on Facebook only. I promised I will do my best to come up with something similar for YoutTube, came up with something even better: This one is like an integrated 3D version of that experiment, and can be expanded, no theoretical limits to it.
But on the original post you can read more details evidence on the day-to-day Facebook ripoff and gaslighting of its audience, CLICK HERE TO READ.

Get involved, share this as wide as you can, make and share your own experiments, let’s crash this monster and its stock market value by outing its schemes!

Imagine getting 115k likes and no heart 😀 What numbers do you see? Check it here

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! Articles can always be subject of later editing as a way of perfecting them

I try to contribute fresh angles and/or fresh information with every Silview.media report, I want my audience to come here for extra-value. I was often asked to write more on the US presidential elections, but, besides what’s already published, I couldn’t find any scoop of my own, that didn’t already look obvious about this coup orchestrated with support from the globalist elites and China.

Until recently.

#ItalyGate is a serious thing now, worth all of our attention, at least as of 6th of January. So I made this video summary for our Youtube channel and everyone who still lives under a rock. While working on it, something struck me, something that hits at the core of this crisis. Watch it, then read my take on it below, please!

UPDATE; YOUTUBE WAS QUICK TO DELETE THE VIDEO, BUT YOU STILL CAN WATCH IT ON BRIGHTEON, or on BITCHUTE!
Soon on more platforms 😉
What they’re doing is like cleaning up all unaligned 9/11 videos.

What struck me, but not in a striking manner, if you catch my drift, is that everyone fell for the “you can’t prove the theft” argument and now they all parrot it. I heard it before from Republicans, but I took it as anecdotal stupidity or shilling. Editing this I realized I’ve never heard a rebuttal to it.

We urgently need more intellectual exercise before the school bus hits us.
We shouldn’t have ever gotten to the point where I have to explain this, but here’s a very simple exercise:

Everyone agrees that the government should ensure certain levels of trustworthiness and safety for the electoral process. It’s the procedure . At least in any country where they hope to sell this farce called “democracy”, because they understand popular trust in the representatives is the force that keeps things together. It’s the same factor that sets the value of a currency: confidence. And if that’s not the case with the US legal system, there’s your societal tumor right there, call the surgeon general! But as far as I know, on paper, US has ok standards.

So not having a dead people voting is, or should be, and is, part of the procedure.
Trumpers got their actions dismissed mostly on procedure.
Trumpers may or may not prove the fraud, but they surely have proven the electoral procedure was a joke and if you have the will to defraud it, there’s nothing to stop you, it’s almost like some local governments encouraged it.
Yet Trumpers can’t click that they won on procedure already, regardless the fraud! They’ve thoroughly proven system failure, they didn’t have elections, that circus didn’t meet ANY standards, and only a recount can change that.
Bonus: losing in the official count and exposing the fraud excludes trumpers from the list of fraud perpetrators, points at Biden. More than a strong suspect.

And only after this discussion, #Italygate comes to prove #Italydidit, statistics to prove impossible happened, witnesses to match events with the data, and so forth… But it’s not needed, they already have a sufficient reason to re-set the record straight
If they don’t solve those earlier principles, everyone has already lost at life, whether they win the elections or not. More than likely, everyone will end up stepping on a land mine they planted for others.

This, in my books, spells total intellectual failure on both sides in this US election, that was below the levels of Ukraine or Belarus. Like how do you even get hypnotized by your enemies when they’re nothing but commie-zombie-one-trick-ponies who do nothing but invert reality at semantic level?! How do you get mentally paralyzed to the point of not being able to respond “you didn’t prove the theft” except by adopting the stance?! People tripping balls about 5D chess can’t follow or form a basic two-step linear (2D) logic.
The existence of “you didn’t prove the theft” argument, and of this article as well, testifies once again, one way or another, that at the core of the current crisis sits a mass intellectual collapse. And the only cure is more intellectual exercise, like this post, even when it fails.

This is re-purposed, but doesn’t it work perfectly?

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! Articles can always be subject of later editing as a way of perfecting them

Under history’s microscope, HIV and Covid-19 look very similar: mostly inferred, never isolated and purified in a lab, very poorly tested, overhyped by mainstream media and extremely profitable, not only financially, but also in terms of population control.

Since Fauci wouldn’t lie to us and participate in some conspiracies that target mostly sexual and racial minorities, we can only call these “a series of amazing coincidences”.
There’s so many of them that this projected 1h documentary might turn into a mini-series, I haven’t finished reviewing all of the testimonies and I’ve just started editing.
Show some love sharing the F out of this cuz I’m on the verge of burnout here going through a mountain of evidence that needs structure and many many hours of editing! 😉
If you want to support and speed up the making of this documentary, possibly mini-series, please share our content or hit the Donate button to Paypal us.
We will deliver ASAP anyway, but the amount of evidence is staggering and our equipment is not really fast. If you help us with the promo or donate for gear funds, we can improve our performance, I personally can’t find more hours in the day to work, thank you!
Below is the most consistent trailer you’ve seen lately and it’s really just a peak into it.

Also read:
EXCLUSIVE: GATES, FAUCI AND SLAOUI HAVE LONG BEEN COOKING AND SELLING SCANDALOUS VACCINES TOGETHER. IT’S A CARTEL

LOOKING FOR A GOOD BOOK? TRY “FAUCI: THE BERNIE MADOFF OF SCIENCE AND THE HIV PONZI SCHEME THAT CONCEALED THE CHRONIC FATIGUE SYNDROME EPIDEMIC”

Let me help with the larger context…

BONUS

HSBC is a Chinese bank and…
…HSBC is also involved with Dominion voting, among others…

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By Gina Kolata, New York Times, Jan. 22, 2007

Dr. Brooke Herndon, an internist at Dartmouth-Hitchcock Medical Center, could not stop coughing. For two weeks starting in mid-April last year, she coughed, seemingly nonstop, followed by another week when she coughed sporadically, annoying, she said, everyone who worked with her.Before long, Dr. Kathryn Kirkland, an infectious disease specialist at Dartmouth, had a chilling thought: Could she be seeing the start of a whooping cough epidemic?

Dr. Brooke Herndon of Dartmouth-Hitchcock Medical Center, shown at left this month, was told last spring that she appeared to have whooping cough.
Dr. Brooke Herndon of Dartmouth-Hitchcock Medical Center, shown at left this month, was told last spring that she appeared to have whooping cough.Credit…Jon Gilbert Fox for The New York Times

By late April, other health care workers at the hospital were coughing, and severe, intractable coughing is a whooping cough hallmark. And if it was whooping cough, the epidemic had to be contained immediately because the disease could be deadly to babies in the hospital and could lead to pneumonia in the frail and vulnerable adult patients there.

It was the start of a bizarre episode at the medical center: the story of the epidemic that wasn’t.

For months, nearly everyone involved thought the medical center had had a huge whooping cough outbreak, with extensive ramifications. Nearly 1,000 health care workers at the hospital in Lebanon, N.H., were given a preliminary test and furloughed from work until their results were in; 142 people, including Dr. Herndon, were told they appeared to have the disease; and thousands were given antibiotics and a vaccine for protection. Hospital beds were taken out of commission, including some in intensive care.

Then, about eight months later, health care workers were dumbfounded to receive an e-mail message from the hospital administration informing them that the whole thing was a false alarm.

Not a single case of whooping cough was confirmed with the definitive test, growing the bacterium, Bordetella pertussis, in the laboratory. Instead, it appears the health care workers probably were afflicted with ordinary respiratory diseases like the common cold.

Now, as they look back on the episode, epidemiologists and infectious disease specialists say the problem was that they placed too much faith in a quick and highly sensitive molecular test that led them astray.

Infectious disease experts say such tests are coming into increasing use and may be the only way to get a quick answer in diagnosing diseases like whooping cough, Legionnaire’s, bird flu, tuberculosis and SARS, and deciding whether an epidemic is under way.

There are no national data on pseudo-epidemics caused by an overreliance on such molecular tests, said Dr. Trish M. Perl, an epidemiologist at Johns Hopkins and past president of the Society of Health Care Epidemiologists of America. But, she said, pseudo-epidemics happen all the time. The Dartmouth case may have been one the largest, but it was by no means an exception, she said.

There was a similar whooping cough scare at Children’s Hospital in Boston last fall that involved 36 adults and 2 children. Definitive tests, though, did not find pertussis.“It’s a problem; we know it’s a problem,” Dr. Perl said. “My guess is that what happened at Dartmouth is going to become more common.

”Many of the new molecular tests are quick but technically demanding, and each laboratory may do them in its own way. These tests, called “home brews,” are not commercially available, and there are no good estimates of their error rates. But their very sensitivity makes false positives likely, and when hundreds or thousands of people are tested, as occurred at Dartmouth, false positives can make it seem like there is an epidemic.

“You’re in a little bit of no man’s land,” with the new molecular tests, said Dr. Mark Perkins, an infectious disease specialist and chief scientific officer at the Foundation for Innovative New Diagnostics, a nonprofit foundation supported by the Bill and Melinda Gates Foundation. “All bets are off on exact performance.

”Of course, that leads to the question of why rely on them at all. “At face value, obviously they shouldn’t be doing it,” Dr. Perl said. But, she said, often when answers are needed and an organism like the pertussis bacterium is finicky and hard to grow in a laboratory, “you don’t have great options.”

Waiting to see if the bacteria grow can take weeks, but the quick molecular test can be wrong. “It’s almost like you’re trying to pick the least of two evils,” Dr. Perl said.At Dartmouth the decision was to use a test, P.C.R., for polymerase chain reaction. It is a molecular test that, until recently, was confined to molecular biology laboratories.

“That’s kind of what’s happening,” said Dr. Kathryn Edwards, an infectious disease specialist and professor of pediatrics at Vanderbilt University. “That’s the reality out there. We are trying to figure out how to use methods that have been the purview of bench scientists.

”The Dartmouth whooping cough story shows what can ensue.

To say the episode was disruptive was an understatement, said Dr. Elizabeth Talbot, deputy state epidemiologist for the New Hampshire Department of Health and Human Services.

“You cannot imagine,” Dr. Talbot said. “I had a feeling at the time that this gave us a shadow of a hint of what it might be like during a pandemic flu epidemic.

”Yet, epidemiologists say, one of the most troubling aspects of the pseudo-epidemic is that all the decisions seemed so sensible at the time.

Dr. Katrina Kretsinger, a medical epidemiologist at the federal Centers for Disease Control and Prevention, who worked on the case along with her colleague Dr. Manisha Patel, does not fault the Dartmouth doctors.

“The issue was not that they overreacted or did anything inappropriate at all,” Dr. Kretsinger said. Instead, it is that there is often is no way to decide early on whether an epidemic is under way.

Before the 1940s when a pertussis vaccine for children was introduced, whooping cough was a leading cause of death in young children. The vaccine led to an 80 percent drop in the disease’s incidence, but did not completely eliminate it. That is because the vaccine’s effectiveness wanes after about a decade, and although there is now a new vaccine for adolescents and adults, it is only starting to come into use. Whooping cough, Dr. Kretsinger said, is still a concern.

The disease got its name from its most salient feature: Patients may cough and cough and cough until they have to gasp for breath, making a sound like a whoop. The coughing can last so long that one of the common names for whooping cough was the 100-day cough, Dr. Talbot said.

But neither coughing long and hard nor even whooping is unique to pertussis infections, and many people with whooping cough have symptoms that like those of common cold: a runny nose or an ordinary cough.

“Almost everything about the clinical presentation of pertussis, especially early pertussis, is not very specific,” Dr. Kirkland said.

That was the first problem in deciding whether there was an epidemic at Dartmouth.

The second was with P.C.R., the quick test to diagnose the disease, Dr. Kretsinger said.

With pertussis, she said, “there are probably 100 different P.C.R. protocols and methods being used throughout the country,” and it is unclear how often any of them are accurate. “We have had a number of outbreaks where we believe that despite the presence of P.C.R.-positive results, the disease was not pertussis,” Dr. Kretsinger added.

At Dartmouth, when the first suspect pertussis cases emerged and the P.C.R. test showed pertussis, doctors believed it. The results seem completely consistent with the patients’ symptoms.

“That’s how the whole thing got started,” Dr. Kirkland said. Then the doctors decided to test people who did not have severe coughing.

“Because we had cases we thought were pertussis and because we had vulnerable patients at the hospital, we lowered our threshold,” she said. Anyone who had a cough got a P.C.R. test, and so did anyone with a runny nose who worked with high-risk patients like infants.

“That’s how we ended up with 134 suspect cases,” Dr. Kirkland said. And that, she added, was why 1,445 health care workers ended up taking antibiotics and 4,524 health care workers at the hospital, or 72 percent of all the health care workers there, were immunized against whooping cough in a matter of days.

“If we had stopped there, I think we all would have agreed that we had had an outbreak of pertussis and that we had controlled it,” Dr. Kirkland said.

But epidemiologists at the hospital and working for the States of New Hampshire and Vermont decided to take extra steps to confirm that what they were seeing really was pertussis.

The Dartmouth doctors sent samples from 27 patients they thought had pertussis to the state health departments and the Centers for Disease Control. There, scientists tried to grow the bacteria, a process that can take weeks. Finally, they had their answer: There was no pertussis in any of the samples.

“We thought, Well, that’s odd,” Dr. Kirkland said. “Maybe it’s the timing of the culturing, maybe it’s a transport problem. Why don’t we try serological testing? Certainly, after a pertussis infection, a person should develop antibodies to the bacteria.”They could only get suitable blood samples from 39 patients — the others had gotten the vaccine which itself elicits pertussis antibodies. But when the Centers for Disease Control tested those 39 samples, its scientists reported that only one showed increases in antibody levels indicative of pertussis.

The disease center did additional tests too, including molecular tests to look for features of the pertussis bacteria. Its scientists also did additional P.C.R. tests on samples from 116 of the 134 people who were thought to have whooping cough. Only one P.C.R. was positive, but other tests did not show that that person was infected with pertussis bacteria. The disease center also interviewed patients in depth to see what their symptoms were and how they evolved.

“It was going on for months,” Dr. Kirkland said. But in the end, the conclusion was clear: There was no pertussis epidemic.

“We were all somewhat surprised,” Dr. Kirkland said, “and we were left in a very frustrating situation about what to do when the next outbreak comes.”Dr. Cathy A. Petti, an infectious disease specialist at the University of Utah, said the story had one clear lesson.

“The big message is that every lab is vulnerable to having false positives,” Dr. Petti said. “No single test result is absolute and that is even more important with a test result based on P.C.R.”As for Dr. Herndon, though, she now knows she is off the hook.

“I thought I might have caused the epidemic,” she said.

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If 2020 was an IQ test, flunking it means repeating it

Due to a little editing error, this important piece of the puzzle is missing from the video. Source.

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#FlattenTheLies Face Mask by Silview
#FlattenTheLies Face Mask by Silview
MASKS ARE BAD FOR YOU, USE THEM ONLY IF YOU HAVE NO BETTER ALTERNATIVE! OR AT PROTESTS. AND IF YOU DO, USE ONE THAT SENDS OUT THE RIGHT MESSAGE.

The World Economic Forum has just published what can only be called the official flyer for the coming Davos 2021 meeting of the World Economic Forum leaders, the masterminds behind The Great Reset. Looks like the awareness campaign we started a few months ago has forced them to publicly assume their insane agenda and allow more public scrutiny.

Download PDF

Remember that thing Justin Trudeau was pushing while saying it’s a “conspiracy theory” that needs to be stopped?

In their own words:

The Davos Agenda will also mark the launch of the World Economic Forum’s Great Reset Initiative and begin the preparation of the Special Annual Meeting in the spring.

Each day will focus on one of the five domains of the Great Reset Initiative:
Monday 25 January: Special Addresses, Leadership Panels
and Impact Sessions on Designing cohesive, sustainable and
resilient economic systems
Tuesday 26 January: Special Addresses, Leadership Panels
and Impact Sessions on Driving responsible industry
transformation and growth
Wednesday 27 January: Special Addresses, Leadership Panels
and Impact Sessions on Enhancing stewardship of our global
commons
Thursday 28 January: Special Addresses, Leadership Panels
and Impact Sessions on Harnessing the technologies of the
Fourth Industrial Revolution
Friday 29 January: Special Addresses, Leadership Panels
and Impact Sessions on Advancing global and regional
cooperation

The Davos Agenda will feature:
– Heads of state and of government from the G20 and international organizations giving special addresses on the state of the world, as well as engaging in dialogue with business leaders from around the world
– Industry leaders and public figures discussing in leadership panels how to advance and accelerate public-private collaboration on critical issues such as COVID-19 vaccination, job creation and climate change, among others
– The Forum’s core communities, including its International Business Council, sharing their insight and recommendations from global, regional and industry initiatives in impact sessions.


The Davos Agenda aims to inform the global public and the Forum’s 25,000,000+ social media followers on the key issues shaping the year ahead. It will also engage over 430 cities in 150 countries that host Global Shapers, a network of young people driving dialogue, action and change.

More than 20,000 members of TopLink, our digital interaction platform, and over 400,000 subscribers to Strategic Intelligence, our world-leading knowledge app, will also be active online throughout the week’s programme.

Live sessions will begin each day as of 08.00 until 19.00 Central European Time (CET).

Last summer, WEF announced the annual gathering of the rich and powerful in the Swiss mountains, will be delayed next year due to the ongoing impact of the COVID-19 pandemic.

The World Economic Forum (WEF) said in a statement that its annual meeting, as Davos is officially known, would be delayed until summer 2021. The event had been due to take place in January.

“The decision was not taken easily, since the need for global leaders to come together to design a common recovery path and shape the ‘Great Reset’ in the post-COVID-19 era is so urgent,” Adrian Monck, managing director of public engagement at the World Economic Forum, said in a statement emailed to media.

“However, the advice from experts is that we cannot do so safely in January.”

Instead, The World Economic Forum will hold this “high-level” digital event. Details of the rescheduled event will be confirmed “as soon as we are assured that all conditions are fulfilled to guarantee the health and safety of our participants and the hosting community,” Monck said.

2020’s attendees included Bill Gates, US President Donald Trump, Google CEO Sundar Pichai, European Central Bank chief Christine Lagarde, German chancellor Angela Merkel, and teenage climate campaigner Greta Thunberg.

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An article titled “m6A RNA modification as a new player in R-loop regulation,” was published in the January 2020 edition of Nature Genetics and widely reported in the scientific community. What we learn from it opens the door for crucially important knowledge in the context of this technology being used for Covid vaccines.

Below I copy/pasted the press release that circulated at the time in several top publications:

“Following a new collaboration between UiO and research groups in Nottingham and Oxford, it has now been revealed that RNA has a direct effect on DNA stability, according to Professor Klungland’s research.

He believes the discovery will provide the health service with an important tool, since many studies have shown that the regulation of modifications to RNA is important for the development of cancer.

If genes that are important for the chemical compound 6-methyladenine are completely removed, this results in neurodegeneration in both mice and humans.

Where and how

In areas of DNA where RNA binds to one of the DNA threads in such a way that the complementary DNA thread becomes the sole thread (R-loop structures), the DNA stability will change if RNA is chemically modified by m6A.

Several research groups are now working together to study what effect this can have on the DNA molecule. We already know that R-loop areas are associated with sequences of DNA containing active genes and that this can lead to chromosomal breakage and the loss of genetic information

Prof. Arne Klungland
Modified RNA has a direct effect on DNA
Credit: University of Oslo

New field of research

Normally, epigenetic gene regulation is studied by examining dynamic modifications of DNA and proteins—so-called epigenetic modifications. The modifications can turn genes on or off without changing the underlying genetic code.

Less than 10 years ago, it was discovered that dynamic modifications also exist in RNA and that these have an important role to play in gene regulation

Important modification

The most common modification is on mRNA is 6-metyladenin (m6A). It has now been shown that this modification is essential for the survival of cells and model (non-human) organisms.

Over the last five years, there has been an enormous increase in the amount of research into RNA modifications—a field called epitranscriptomics.

One of the first studies in this field of research was the result of a collaboration between research groups in Chicago, Beijing and Oslo (Zheng, Dahl et al., Molecular Cell, 2012, 49, 18-29).

End of article citation.
I bolded a few paragraphs to make sure you see what I saw:
RNA modification not only can alter DNA, but it’s been already envisioned as a tool for DNA editing.
This argues the whole BS official narrative that the RNA vaccine technology is inoffensive for the DNA

One of the most remarkable findings of this study is that depletion of YTHDF2 and METTL3 (the writer that deposits m6A) increases levels of γH2AX, a marker of DNA double-strand breaks, thus suggesting that pathological R-loop accumulation in the absence of the m6A RNA-methylation pathway challenges genome integrity. This result is in line with findings from many studies that clearly suggest the potential of R-loops to induce DNA double-strand breaks2. Moreover, dysregulation of R-loops is emerging as a critical factor driving genome instability in a large variety of pathological contexts, including after oncogenic stress12, in cells infected with Kaposi’s sarcoma–associated herpesvirus, in neurological disorders associated with trinucleotide-repeat expansion (such as Huntington’s disease and fragile X syndrome) and in multiple other inherited ataxias (for example, ataxia with oculomotor apraxia 2)2. The use of existing drugs targeting the m6A pathway (for example, inhibitors of FTO) could therefore be considered as a new therapeutic approach to treat R-loop-related diseases13.
Beyond genome stability, the finding that m6A methylation controls R-loop levels across the genome considerably expands the biological functions of the m6A-modification pathway to potentially all R-loop-related functions, including DNA topology (because R-loops have recently been proposed to relieve superhelical stress), immunoglobulin class-switch recombination (and therefore the immune response), replication initiation and transcription1,2,14. Additionally, m6A accumulates at sites of ultraviolet-induced DNA damage6, thus raising the interesting possibility that this modification may also regulate R-loops during DNA repair and thus affect the frequency of chromosomal translocations15.
In summary, the results presented by Abakir et al. unveil an unexpected interplay between RNA modifications (the epitranscriptome) and the maintenance of genome integrity. Re-analysis of the pathological contexts implicating dysregulation of the m6A RNA pathway through the prism of genome instability therefore warrants further investigation (Fig. 1).

m6A RNA modification as a new player in R-loop regulation – Aline Marnef & 
Gaëlle Legube, Nature Genetics

Epitranscriptomics: The new RNA code and the race to drug it

A small group of scientists studying chemical modifications on RNA ushered in the field of epitranscriptomics. Now they’re hoping it will create an entirely new way to treat cancer

by Ryan Cross, Chemical & Engineering News, Feb. 18, 2019 

It’s not every day that a biotech investor stumbles across an entirely new field of science. And frankly, Carlo Rizzuto wasn’t even looking for such a thing. When Rizzuto, a partner at the venture capital firm Versant Ventures, embarked on a scouting trip to New York City in 2014, he was simply hoping to discover academic research that was ripe enough to form the basis of a biotech company.

Rizzuto had an appointment with Samie Jaffrey, an RNA scientist at Weill Cornell Medicine. RNA is often described as a cousin to DNA—the stuff that our genes are made of. One kind of RNA, called messenger RNA, acts as the intermediary code that cells use to transfer information stored in DNA into a set of instructions that cells can easily read for making proteins.

After Rizzuto rejected several of his projects, Jaffrey mentioned a relatively young line of work focused on studying chemical modifications to RNA. In 2012, his lab invented a method to map the location of methyl groups that, for some reason, cells were adding to their mRNA. It was reminiscent of another field, called epigenetics, or the study of chemical modifications made to DNA to turn genes on or off. The entirety of RNA in a cell is called the transcriptome, so Jaffrey dubbed the new field “epitranscriptomics.”

Rizzuto perked up. “This is something that we would be very interested in,” he said.09607-cover-jaffrey.jpgCredit: Gotham TherapeuticsSamie Jaffrey, a professor of pharmacology at Weill Cornell Medicine and cofounder of Gotham Therapeutics, explains the m6A modification on RNA. Jaffrey’s lab invented a technique to map the location of m6A on RNA.

Jaffrey was hesitant. “We’re just doing basic stuff now,” he recalls explaining. His lab, and others, was still trying to figure out how this RNA modification system worked. They were building evidence suggesting that enzymes added and removed these methyl marks to control the fate of mRNA, and thus protein production, but many questions remained. Jaffrey implored: “Carlo, what disease would we be curing if we started a company around epitranscriptomics?”

“It doesn’t matter,” Rizzuto replied. “This is so central to molecular biology; it has to be related to fundamental disease processes.”

Then reality kicked in. Venture capital firms like Rizzuto’s aren’t in the business of funding years of basic research just to see if something like epitranscriptomics is involved in disease. “We were looking at a new paradigm for gene-expression regulation,” Rizzuto recalls, but it was too early to start a company. He and Jaffrey agreed to stay in touch.

Rizzuto’s enthusiasm in 2014 has since percolated among scientists and investors learning about epitranscriptomics. Several groups, including Jaffrey’s, have shown that the epitranscriptomic code—the number and location of chemical modifications across a cell’s RNA—is seriously out of whack in some cancers. And with basic tools in hand to read this previously hidden layer of information in cells, biotech companies are now out to alter it. Three start-ups, including one that Jaffrey and Rizzuto helped found, called Gotham Therapeutics, have launched with more than $110 million in total dedicated to epitranscriptomics drug discovery.

There was a similar reaction to epigenetics more than a decade ago, when it became clear that chemical modifications regulating genes are frequently out of whack in cancer. Companies rushed to develop drugs against proteins responsible for making, removing, and recognizing chemical modifications on genes—often referred to as the writer, eraser, and reader proteins. With the discovery of parallel writer, eraser, and reader proteins working on RNA, epitranscriptomics is looking like a promising, untapped area for drug discovery.

But there’s another parallel to epigenetics that’s less optimistic: thus far, epigenetic drugs have been a disappointment. “Epigenetics turned out to be a lot more complicated than the community originally thought,” says Chuan He, a professor of chemistry at the University of Chicago.

He, a scientific founder of the epitranscriptomics company Accent Therapeutics, has been at the forefront of developing the new study of RNA modifications and their role in disease. He, Jaffrey, and many others are confident that understanding and controlling RNA modifications will provide completely new avenues for treating disease. “What this really offers is a totally new biology,” He says. “And whenever there is a new biology emerging there are always opportunities for therapies.”


EPITRANSCRIPTOMICS, ABRIDGED

A series of discoveries and technical advancements over the past decade has spawned a new field called epitranscriptomics, the study of chemical modifications to RNA, and the proteins that write, erase, and read these modifications. In recent years, studies implicating epitranscriptomic proteins in cancer have led to the launch of three biotech companies dedicated to drugging these proteins.

May 2008: Rupert Fray shows that a methyl-adding enzyme is essential for plant development. The study inspires others to look at RNA modifications.

November 2010: Chuan He proposes new field of RNA epigenetics, suggesting that methyl modifications on RNA can be removed.

October 2011: Chuan He’s lab proves that an enzyme called FTO erases methyl modifications on RNA.

April and May 2012: The labs of Gideon Rechavi (April) and Samie Jaffrey (May) publish the first maps of RNA methyl modifications. Jaffrey coins the word “epitranscriptomics.”

October 2014: Howard Chang’s lab shows that METTL3, which adds methyl groups to RNA, is critical for embryonic stem cell development and differentiation.

June 2016: Storm Therapeutics, founded by University of Cambridge scientists Tony Kouzarides and Eric Miska, raises $16 million to drug proteins that make RNA modifications.

September and November 2017: Independent studies from Samie Jaffrey and colleagues (September) and Tony Kouzarides and colleagues (November) show that METTL3 is elevated in acute myeloid leukemia and that suppressing the enzyme forces the cancer cells to become noncancerous.

May 2018: Accent Therapeutics, cofounded by Chuan He, Howard Chang, and Robert Copeland, raises $40 million.

October 2018: Gotham Therapeutics, cofounded by Samie Jaffrey, launches with $54 million.

February 2019: Evidence builds that epitranscriptomics may be important for cancer immunotherapy. Chuan He shows that deleting a reader protein boosts the efficacy of checkpoint inhibitors in mice.

MAKING A MAP

A series of events beginning in 2008 laid the foundation for epitranscriptomics. That year, while He was studying epigenetic enzymes that remove methyl modifications from DNA, he and University of Chicago biologist Tao Pan began doubting that all these enzymes were really working on DNA as others assumed. The evidence was particularly shaky for one enzyme, called fat mass and obesity-associated protein, or FTO.

But a study coming out of the lab of plant biologist Rupert Fray at the University of Nottingham reinforced He and Pan’s suspicions that RNA modifications were underappreciated. Fray showed that plants missing a methyl-adding enzyme—similar to an enzyme called METTL3 in humans—stopped growing at a specific early stage in their development.

Scientists knew that METTL3 placed a methyl on a specific nitrogen in adenosine, one of the four building blocks of RNA. This modified building block is called N6-methyladenosine, or m6A for short. Beyond m6A, chemists had cataloged some 150 different chemical modifications to RNA in bacteria, plants, and animals. If He could find an enzyme that removed the methyl groups, it would suggest that there was an undiscovered RNA control system in cells, analogous to epigenetic controls in DNA.

In 2010, He coined the phrase “RNA epigenetics” in a commentary that outlined his ideas (Nat. Chem. Biol.DOI: 10.1038/nchembio.482). A year later, He and Pan published evidence showing that the FTO enzyme was an eraser—it removed the methyl modifications made by METTL3 (Nat. Chem. Biol. 2011, DOI: 10.1038/nchembio.687).

METTL3 and FTO are both enzymes, which means they should be pretty straightforward to inhibit with small-molecule drugs. That notion would later be frequently cited by the new epitranscriptomics companies, although it would be several years still before these enzymes were connected to disease.

At first, the significance of these enzymes was lost on many researchers. At Weill Cornell, however, Jaffrey immediately recognized that He’s study was part of a new field that was about to explode. His lab had been working on a method to detect and map m6A across a cell’s mRNA. Jaffrey had also seen Fray’s work on m6A in plants and thought that if the modifications existed in humans, they must be doing something important in us too.

At the time, methods for studying m6A were rudimentary. Researchers could detect the presence of m6A in ground-up globs of mRNA run through common chemistry lab techniques like chromatography or mass spectrometry. “But you had no idea which mRNAs were being modified,” Jaffrey says. No one knew if all mRNA had some m6A or if the methyl modifications were found on only certain transcripts, he adds. “And frankly, it wasn’t even terribly clear that m6A levels changed.”This is so central to molecular biology; it has to be related to fundamental disease processes.Carlo Rizzuto, partner, Versant Ventures

So Jaffrey and Kate Meyer, a postdoc in his lab, developed a technique to figure out which mRNAs contained these modifications. They used commercially available antibodies that attach to m6A to fish out fragments of human mRNA for sequencing (Cell 2012, DOI: 10.1016/j.cell.2012.05.003).

That technique allowed the creation of the first map of m6A. The results were stunning. “We thought that m6A was going to be all over the place, kind of random,” Jaffrey says. Instead, the researchers saw that methyl marks tended to cluster near an area called the stop codon, and only on certain mRNA transcripts. “It was so specific, it just knocked our socks off.”

An even closer inspection revealed that many of the mRNAs containing m6A were linked to differentiation and development, the same functions that were affected in Fray’s stunted plant embryos. “We were amazed,” Jaffrey says.

In April 2012, while Jaffrey and Meyer were waiting for their m6A paper to publish, another group, led by Gideon Rechavi at Tel Aviv University, published its own paper on the use of antibodies to map m6A in mouse and human cells (Nature 2012, DOI: 10.1038/nature11112). “It was met with a lot of skepticism,” says Dan Dominissini, the PhD student in Rechavi’s lab who led the project. “People didn’t get why it was important. It took a year to publish.”

The problem was researchers still hadn’t established a clear link between these RNA modifications and disease, or even basic human biology. Moreover, the field wouldn’t have its name of epitranscriptomics for another three weeks, when Jaffrey and Meyer’s paper describing their m6A-mapping technique was published online in May 2012. Although Jaffrey had been scooped, the back-to-back publications put epitranscriptomics on the radar. The field was poised to explode.


Editing the epitranscriptomic code

The most common RNA modification is N6-methyladenosine (m6A), which is made when a protein complex containing the “writer” enzyme METTL3 adds a methyl group to adenosine. Two different “eraser” enzymes, called ALKBH5 and FTO, can remove a methyl group to turn m6A back into adenosine.Credit: ALKBH5, FTO, and METTL3-METTL14 protein images created with the Protein Data Bank, NGL Viewer

SEARCHING FOR DISEASE

In Chicago, He was positioning his lab as the forefront of epitranscriptomics research. His group discovered that an enzyme called ALKBH5, like FTO, erased methyl marks on RNA, turning m6A back into adenosine. Yet even by 2014, two years after the m6A-mapping methods were published, epitranscriptomics wasn’t getting the recognition, or funding, that He thought it deserved. “People thought it was cute,” He says. “But biologists were not convinced of its significance.”

Epitranscriptomics was now a hot topic. As studies began bubbling up exploring the role of RNA modifications, particularly m6A, in a variety of cells and species, investors started putting money into the field. In June 2016, a British start-up called Storm Therapeutics raised $16 million and became the first company dedicated to tackling the new RNA epigenetics.

Although Storm was several years in the making, it wasn’t clear what diseases the company would be curing. Two University of Cambridge scientists, Tony Kouzarides and Eric Miska, began discussing the idea for the company back in 2012, when they had published work on obscure enzymes that chemically modify microRNAs, which regulate the function of other RNAs.

Although the enzymes were linked to cancer, at least in cells growing in a dish, the microRNA studies went largely unnoticed. Kouzarides and Miska thought more undiscovered links between RNA modifications and cancer must exist, but it took a few years to find investors willing to bet on their hypothesis. “I don’t think that there was a huge amount of actual data; it was just the belief that there must be,” Storm’s CEO, Keith Blundy, says. “The idea that all of these chemical modifications on RNA weren’t dysregulated or mutated or changed in cancer was almost unthinkable.”

That belief, which echoes the sentiment that Versant Ventures’ Rizzuto expressed in Jaffrey’s office in 2014, was about to be validated. In the second half of 2016, studies began linking reader and writer proteins to cancer. Jaffrey saw the evidence firsthand in an ongoing study he was conducting in blood cancer. The implications for drug discovery were becoming clear. He reached out to Rizzuto. It was time to move forward.

ANNOTATIONS IN THE BLOOD

The common thread running through epitranscriptomics research was its link to cell differentiation and development. Chang’s and Rechavi’s stem cell studies on m6A gave several research labs—including He’s, Jaffrey’s, and Kouzarides’s—the idea to look at the role of these RNA modifications in a deadly blood cancer called acute myeloid leukemia.

Leukemia is essentially a disease of dysfunctional differentiation. Healthy people’s bones are filled with hematopoietic stem cells that produce white blood cells. In leukemia, these stem cells go haywire. They proliferate and displace other blood cells because they can’t differentiate, or mature, into normal white blood cells.

In December 2016, He’s lab, together with several collaborators, showed that tissue samples taken from people with certain kinds of acute myeloid leukemia displayed high levels of the enzyme FTO—which, five years earlier, He had discovered is an m6A eraser (Cancer Cell 2016, DOI: 10.1016/j.ccell.2016.11.017). A few months later, with a different set of collaborators, He showed that levels of the methyl-removing enzyme ALKBH5 were elevated in glioblastoma stem cells (Cancer Cell 2017, DOI: 10.1016/j.ccell.2017.02.013).09707-cover-rnamethyl.jpgCredit: Journal of the American Chemical SocietyA surface (mesh) structure of an RNA duplex (sticks) with the methyl modification of m6A (balls).

At the beginning of 2017, Lasky, the Column Group investor, reached out to He. Now that epitranscriptomic enzymes were tied to cancer, Lasky’s firm wanted to start a drug company to control RNA modifications. With the new cancer data in hand, He felt that the time was right.

The investors also knew about a publication in the works from Jaffrey and leukemia expert Michael Kharas at Memorial Sloan Kettering Cancer Center. The Column Group and Versant Ventures worked together for a time to begin forming a single epitranscriptomics company with several of the academic leaders. During the summer of 2017 however, the different players split into two camps. The Column Group brought on He and Chang as academic cofounders of Accent Therapeutics. Versant Ventures named Jaffrey the academic founder of Gotham Therapeutics.

While Accent and Gotham were still in stealth mode, Jaffrey published a study showing that genetic mutations led to fixed, elevated levels of METTL3 in acute myeloid leukemia, keeping white blood cells from forming. By reducing METTL3 levels, leukemia cells could be coaxed into undergoing differentiation to become noncancerous cells that eventually die (Nat. Med. 2017, DOI: 10.1038/nm.4416). “It was remarkable because we didn’t even need complete inhibition of METTL3,” Jaffrey says.

Two months later, Kouzarides’s lab at the University of Cambridge published similar results, with additional details on what METTL3 was doing in these cells (Nature 2017, DOI: 10.1038/nature24678). In leukemia, elevated METTL3 encouraged the production of proteins linked to cancer. “It is feeding the cell the very proteins that are driving tumorigenesis,” Gotham CEO Lee Babiss says.

Epitranscriptomics now had drug targets, diseases, and high-profile studies. After recruiting additional investors, Accent launched with $40 million in May 2018, and Gotham launched with $54 million in October. Storm Therapeutics is in the process of raising approximately $65 million for its second round of cash from investors. Although none of these companies will name their targets or first diseases they will attempt to treat, conversations with the companies’ CEOs suggest that developing inhibitors of METTL3 is a goal for all three.

Drug designers have a lot of experience inhibiting enzymes, making METTL3 an attractive first target. But its activity may not be straightforward, says Yunsun Nam, a biophysicist at the University of Texas Southwestern Medical Center. METTL3 grabs the methyl group it adds to RNA from S-adenosylmethionine (SAM), a molecule used by several other enzymes. Companies’ compounds will need to avoid inhibiting these other enzymes as well, she explains.

Nam thinks a workaround could be targeting a protein called METTL14, which is attached to METTL3 as part of a larger m6A-writing complex. “METTL3 and METTL14 are very dependent on each other for stability,” she says.

Even if the companies can develop selective METTL3 inhibitors, it’s unclear how many people would benefit from them. While the leukemia studies by Jaffrey and Kouzarides showed that m6A levels are too high, He’s leukemia and glioblastoma studies showed the opposite, that m6A levels are too low. Other studies have suggested more contradictory results—including that m6A levels may be too high in glioblastoma. In other words, when developing therapies, it will be crucial to know the epitranscriptomic state of one’s cancer cells. Otherwise, giving the wrong person a METTL3 inhibitor might make things worse.

“That’s a possibility,” Robert Copeland, the president and chief scientific officer of Accent, acknowledges. The challenge for Accent and other companies will be to figure out which subset of people with leukemia would benefit from a METTL3 inhibitor, to lower m6A levels, and which would benefit from an FTO inhibitor, to raise m6A levels, Copeland explains. “If the pendulum swings too much one way or too much the other way, you can cause disease.”09707-cover-copelandcxd.jpgCredit: Accent TherapeuticsRobert Copeland, president and chief scientific officer of Accent Therapeutics

EPI-EXPANSION

Although the leaders of Accent, Gotham, and Storm are being secretive about their strategies, they all hint that the potential scope of epitranscriptomics drug discovery is much bigger than just targeting METTL3.

In addition to the m6A erasers, a growing body of work is uncovering the importance of the m6A readers. Earlier this month, He’s lab showed that an m6A reader protein called YTHDF1 is an important control switch in the immune system and that inhibiting it might dramatically boost the efficacy of existing checkpoint inhibitors, a popular class of cancer immunotherapy (Nature 2019, DOI: 10.1038/s41586-019-0916-x). “I think a lot of immunotherapy companies will jump into epitranscriptomics once they read the paper,” He says.

And this isn’t the first known link between epitranscriptomics and immunotherapy, Accent’s Copeland says. His firm has been studying an enzyme called ADAR1—which stands for adenosine deaminase acting on RNA—that modifies adenosine bases in RNA. Studies from academic labs show that some tumors depend on ADAR1 in ways that normal cells do not. One study suggests that blocking ADAR1 could make certain drug-resistant cancers vulnerable to checkpoint inhibitors (Nature 2018, DOI: 10.1038/s41586-018-0768-9).

Other labs entering the fray are uncovering new proteins that read, write, and erase RNA modifications, with links to additional types of cancer and other diseases. The scope of epitranscriptomics could be enormous. “That’s what excites us about the field,” says Blundy, Storm’s CEO. “There are many, many RNA pathways that are regulated through modifications.”

The discoveries aren’t all coming smoothly, however. For example, Jaffrey claims that the main target of the eraser enzyme FTO isn’t actually m6A but a slightly different modification, called m6Am. Others disagree. “There is still some debate, but that is the normal trajectory for a field, especially in the early days,” Jaffrey says.

The field also still has technical hurdles. “Right now the methods to map and detect m6A are crude,” Jaffrey admits. Existing methods require large sample sizes and are ineffective at quantifying how m6A levels change over time on particular mRNA transcripts. His lab is now working on ways to better quantify m6A to diagnose or predict diseases in the clinic. Such tools will be critical for recruiting the right people into clinical studies testing inhibitors of epitranscriptomic proteins.

Another issue is the lack of publicly available small-molecule inhibitors for studying epitranscriptomic proteins. “We don’t even have an inhibitor for research,” says Dominissini, who has also developed new RNA-modification-mapping techniques and now runs his own epitranscriptomics lab at Tel Aviv University. Right now, researchers have to use genetic techniques to remove or block production of writer, eraser, and reader proteins, but what the field really needs are simple small molecules to test the hypotheses that these proteins will make good drug targets, he says. Of course, that’s what the companies are working on.

A similar lack of compounds stalled epigenetics drug discovery more than a decade ago. Pioneers in the epitranscriptomics field are unfazed by these parallels. “I don’t think there is a relationship between the success or failure of an epigenetics drug to an epitranscriptomics drug,” Jaffrey says.

The scientists and companies in the field are running full speed ahead. Hundreds of labs have cited papers from Dominissini, He, and Jaffrey, and all can point to several ongoing studies investigating the role of RNA modifications in other diseases. “It reflects how fast people jumped into the field,” He says. “Epitranscriptomics is booming.”

RNA AS A PATHWAY TO THE BRAIN

A 2018 study from the Scripps Research laboratory of Sathyanarayanan Puthanveettil, PhD, peers deep within the nucleus of developing brain cells and finds that long noncoding RNAs play an important role in the healthy functioning and maintenance of synapses, the communication points between nerve cells in the brain.

“Long noncoding RNAs are often described as ‘the dark matter of the genome.’ So, systematic interrogation of their function will illuminate molecular mechanisms of brain development, storage of long-term memories and degradation of memory during aging and dementia,” Puthanveettil says.

RNA are the master regulators of the cell, tiny chains of nucleotides that read, transcribe and regulate expression of DNA, and build proteins. While scientists have gained great insights recently into the genetics underpinning how brain cells reach out and communicate with each other, the role of noncoding RNA is poorly understood. Research suggests that the longest of these noncoding RNA, those over 200 nucleotides long, help determine which genes are activated and operating in brain cells at various times. But which ones?

Writing in the journal Proceedings of the National Academy of Sciences, Puthanveettil and his colleagues on Scripps Research’s Florida campus report that a specific long non-coding RNA, GM12371, controls expression of multiple genes involved in nervous system development and functioning. Furthermore, it affects the developing neurons’ shape and ability to signal.

In mouse hippocampal cells, learning-related signaling upregulates GM12371, while its reduction produces inactive neurons, ones with sparse branches.

Together, the results suggest that healthy growth and development of brain cells and brain circuits depends not just upon specific proteins but also upon specific long noncoding RNAs, which scientists are now beginning to explore.

What role GM12371 dysfunction may play in diseases of the brain and nervous system demands further study, Puthanveettil says.

“Both coding and noncoding RNAs are increasingly viewed as druggable targets. Identifying their specific roles in the fundamental biology of functioning of neural circuits might eventually open new ways of treating neuropsychiatric disorders, such as autism and Alzheimer’s disease,” Puthanveettil says.

A Chinese team of researchers furthers these findings one year later:

“In the emerging field of epitranscriptomic mechanisms, mRNA m6A modification has potential role in learning and memory. It regulates physiological and stress-induced behavior in the adult mammalian brain, and augments the strength of weak memories. As a newly identified element in the region-specific gene regulatory network in the mouse brain, mRNA m6A modification plays a vital role in the death of dopaminergic neuron.
Mettl3-mediated RNA m6A modification has the direct effect on regulating hippocampal-dependent long-term memory formation. The decrease of Mettl3 in the mice hippocampus may reduce its memory consolidation, and adequate training or restoration would restore the ability of learn and memory.”

“The role of mRNA m6A methylation in the nervous system”, Cell & Bioscience, 2019

From the same Chinese study quoted above:
Epitranscriptomics, also known as “RNA epigenetics”, is a chemical modification for RNA regulation [1]. According to its function, RNA can be divided into two broad categories, including encoding protein mRNA and non-coding RNA. With the deep research of epitranscriptomics, the researchers found methylation modification on mRNA, which is involved in the regulation of eukaryotic gene expression [2,3,4].
The mRNA is a type of RNA with genetic information synthesized by DNA transcription, which acts as a template in protein synthesis and determines the amino acid sequence of the peptide chain [5]. It is an important RNA in the human body. The methylation is the process of catalytically transferring a methyl group from an active methyl compound such as S-adenosylmethionine (SAM) to another compound, which can chemically modify certain proteins or nucleic acids to form a methylated product [6]. In biological systems, methylation influences heavy metal modification, regulation of gene expression, regulation of protein function, RNA processing, etc. [7]. At the early 1970s, scientists discovered the presence of the methylation modification in mRNA [89]. The mRNA methylation modification mainly located in the nitrogen atom of the base group to form m6A, which is enriched in long exons and overrepresented in transcripts with alternative splicing variants [10]. The mRNA methylation modifications also include 5-methylcytosine (m5C), N1-methyladenosine (m1A), 5-hydroxymethylcytosine (5hmC), N6, 2′-O-dimethyladenosine (m6Am), 7-methylguanine (m7G) (Fig. 1). These modifications can affect regulation of various biological processes, such as RNA stability and mRNA translation, and abnormal mRNA methylation is linked to many diseases
“.

Another US study from 2018 deals with “Role of RNA modifications in brain and behavior” and reveals that:
“Much progress in our understanding of RNA metabolism has been made since the first RNA nucleoside modification was identified in 1957. Many of these modifications are found in noncoding RNAs but recent interest has focused on coding RNAs. Here, we summarize current knowledge of cellular consequences of RNA modifications, with a special emphasis on neuropsychiatric disorders. We present evidence for the existence of an “RNA code,” similar to the histone code, that fine-tunes gene expression in the nervous system by using combinations of different RNA modifications. Unlike the relatively stable genetic code, this combinatorial RNA epigenetic code, or epitranscriptome, may be dynamically reprogrammed as a cause or consequence of psychiatric disorders. We discuss potential mechanisms linking disregulation of the epitranscriptome with brain disorders and identify potential new avenues of research”.

But the most important take out from this latter study, for me, is the final conclusion that stresses the need for larger data-bases to advance the research. I find it important because data bases need samples. And samples are often collected with swabs, like those used for Covid testing.

“With the development of more and better epitranscriptome sequencing technologies there will be a need to analyze large sequencing datasets. New bioinformatic tools are needed to supplement the current data analysis pipelines which were initially designed to analyze chromatin immunoprecipitation sequencing (ChIP seq) data. These new tools will need to take into account the complications caused by differential splicing, and amplification bias induced during reverse transcription as well as integrate multiple RNA modifications within the same molecule of RNA, across the entire transcriptome. A comprehensive database for curating and sharing epitranscriptomic data should be established to standardize the experimental and computational procedures that are used in different studies.123 We envision that in the not so distant future many new molecular and bioinformatic tools will become available to facilitate rapid advancements in the field of epitranscriptomics.”

Role of RNA modifications in brain and behavior” – Y. Jung and D. Goldman

Actually China and US have been collaborating for quite a while in getting ahead of the curve in RNA therapies. In 2017, a mixed research team from the two countries noted in a study:

“Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5′ cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N⁶-methyladenosine (m⁶A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it’s clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.”

Dynamic RNA Modifications in Gene Expression Regulation, 2017, Cell magazine

It’s obvious we’re dealing with an already vast scientific domain that can expand far and wide and has serious positive and negative potential for the human species.
And that’s a completely different story than what the establishment is giving you on the RNA vaccines and technologies.

In closure, I’ll quote none other than the Oxford University, the world-famous covid vaccine developers who have been also at the core of this technology, as proven by their 2018 study “m6A modification of non-coding RNA and the control of mammalian gene expression

“For more than forty years we have known that like DNA, RNA is chemically modified, with evidence of RNA modifications identified from viruses to Arabidopsis, mouse and man. Characterisation of highly abundant modified tRNA and rRNA first informed us of the plethora of structural and functional roles for modified RNA. “

HeatherCoker, GuifengWei, NeilBrockdorff – Department of Biochemistry, University of Oxford

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! Articles can always be subject of later editing as a way of perfecting them

In 2000 the Washington Post published a major exposé accusing Pfizer of testing a dangerous new antibiotic called Trovan on children in Nigeria without receiving proper consent from their parents. The experiment occurred during a 1996 meningitis epidemic in the country. In 2001 Pfizer was sued in U.S. federal court by thirty Nigerian families, who accused the company of using their children as human guinea pigs.

The trials led to the deaths of 11 children. Dozens more were left disabled.Pfizer’s Unapproved Clinical Trial The unauthorized trial involved tests on 200 children with Pfizer’s antibiotic Trovan. Source: BBC News

In 2011, Pfizer paid $700,000 to four families who lost children during the Trovan trials.

In addition, the company set up a $35 million fund for those affected by Trovan. Pfizer also agreed to sponsor health projects in Kano, Nigeria.

The question that boggled many analysts: How din Pfizer manage to settle so low, after Kano initially filed for $7BILLION damages?

Timeline of the legal case

2006: a panel of Nigerian medical experts concluded that Pfizer had violated international law.

2007: Charges

Source

“After more than a decade of silence, the Nigerian government has decided to sue Pfizer, seeking $7bn (£3.5bn) in damages for the families of children who allegedly died or suffered side-effects in the experiment. Kano State government has also filed separate charges against Pfizer.
But Mr Sani says compensation will not be enough.
“In addition to the compensation, they should be killed like the children they have killed,” he says.
The Pfizer experiment was cited by many as a reason for the mass rejection of polio vaccinations in many parts of northern Nigeria in recent years.
Some local Islamic preachers said there was a western plot to sterilise Muslim women. After several tests were carried out to proving the vaccine’s safety, the programme has now been resumed.
Whether the families ever receive compensation, it will never be enough to bring back Anas’s lost dreams of becoming a soldier.” – BBC

2009: The Nigerian state of Kano settled with Pfizer for $75 million in July 2009. Details of the federal settlement were never reported.

At the end of January 2009, a New York appeal court ruled Mr Etigwe and Mr Altschuler’s case could be heard in the US. The Connecticut attorney says it could still go ahead. “Our case is firmly embedded in the US … so a Nigerian settlement does not foreclose our case. But this is very good news. I’m glad we remained the constant gardener and could see this come to fruition.”

2011:

Eleven of the children died and many more, it is alleged, later suffered serious side-effects ranging from organ failure to brain damage. But with meningitis, cholera and measles still raging and crowds still queueing at the fence of the camp, the Pfizer team packed up after two weeks and left.

That would probably have been an end to the story if it weren’t for Pfizer employee, Juan Walterspiel, the Independent writes in 2014.
” About 18 months after the medical trial he wrote a letter to the then chief executive of the company, William Steere, saying that the trial had “violated ethical rules”. Mr Walterspiel was fired a day later for reasons “unrelated” to the letter, insists Pfizer.

2014: Pfizer to pay only $163.50m after deaths of Nigerian children in drug trial experiment!

Out of court settlement in the case inspired ‘The Constant Gardener” movie.

The company claims only five children died after taking Trovan and six died after receiving injections of the certified drug Rocephin. The pharmaceutical giant says it was the meningitis that harmed the children and not their drug trial. But did the parents know that they were offering their children up for an experimental medical trial?

“No,” Nigerian parent Malam Musa Zango said. He claims his son Sumaila, who was then 12 years old, was left deaf and mute after taking part in the trial. But Pfizer has denied this and says consent had been given by the Nigerian state and the families of those treated. It produced a letter of permission from a Kano ethics committee. The letter turned out to have been backdated and the committee set up a year after the original medical trial.

At stake at one point in 2013 was more than $8bn in punitive damages being sought in a string of cases, as well as potential jail terms in Nigeria for several Pfizer staff. “There has been a complex web of cases with proceedings in Connecticut, New York, Lagos, Abuja and Kano,” Mr Etigwe said. “The strategy of big companies when they are dealing with smaller opponents is to stretch the process, to overwhelm us until we are ready to accept whatever they want to offer.”

Trovan never became the blockbuster that Pfizer had hoped for and it is no longer in production. The EU has banned the drug and it has been withdrawn from sale in the US.

It appears that Pfizer has finally ended the public relations nightmare with Friday’s settlement. But the Trovan battle may not be over yet.

2015: Nigerian govt withdraws civil lawsuit in preparation for new case against Pfizer. New case never followed.

Reuters: Nigerian government lawyers have withdrawn a 7 (b) billion US dollar civil lawsuit against US drugmaker Pfizer on Friday in preparation for filing a new case, with new material they believe will strengthen their case. The criminal case, is one of three currently being brought in Nigeria against the company. The government has accused Pfizer, the world’s largest pharmaceutical company, of taking advantage of a 1996 meningitis epidemic to test an experimental drug without authorisation or full understanding of the families involved – allegedly contributing to the deaths of some of the children and making others sick. Pfizer denies wrongdoing. The civil case is in addition to a federal criminal case and separate from civil and criminal cases launched at the state level in the northern state of Kano. All the cases stem from the same mid-1990s drug study. Pfizer treated 100 meningitis-infected children with an experimental antibiotic, Trovan. Another 100 children, who were control patients in the study, received an approved antibiotic, ceftriaxone – but the dose was lower than recommended, the families’ lawyers alleged. Up to 11 children in the study died, while others suffered physical disabilities and brain damage. Pfizer always insisted its records show none of the deaths was linked to Trovan or substandard treatment. Barrister Abdulateff Thomas said that he did not accept any of the company’s excuses that the studies were conducted through a deal with the Nigerian government. “If there was any deal at all it was made by an individual against the interest of the government, against the interest of a nation,” he said. “Could they do that deal in America? Can they do it in the UK? Or in any of the European countries? No,” he added. Speaking before the latest development, he added that he did not believe that Pfizer would suffer any consequences as a result of the – now withdrawn – lawsuit. “Nothing is going to happen to Pfizer, if anyone tells you otherwise. Pfizer is going to remain strong, he said. Authorities in Kano state are blaming the Pfizer controversy for widespread suspicion of government public health policies, particularly the global effort to vaccinate children against polio. Islamic leaders in largely Muslim Kano had seized on the Pfizer controversy as evidence of a US-led conspiracy. Vaccination programmes restarted in Nigeria in 2004, after an 11-month boycott.

So we have over a decade of legal battles in which Pfizer saves about $7billion in penalties. As spectacular as it is mysterious. No one has ever revealed an official explanation that satisfies that kind of success, you would expect some solid steel evidence that crushed the cases and the demands from the plaintiffs, but that is unheard of.

The answer might be hidden is some classified U.S. State Department cables made public in 2010 by Wikileaks, which indicated that Pfizer had hired investigators to dig up dirt on Nigeria’s former attorney general as a way to get leverage in one of the remaining cases. Pfizer had to apologize over the revelation in the cables that it had falsely claimed that the group Doctors Without Borders was also dispensing Trovan during the Nigerian meningitis epidemic. And by doing so, validated the cables.

A Pfizer representative in a phone interview with Washington Post declined to discuss specifics of the cable or Liggeri’s alleged comments. In its written statement last week, Pfizer said it negotiated the confidential settlement with the federal government “in good faith and its conduct in reaching that agreement was proper.” Pfizer said it had agreed to pay the legal fees and expenses incurred by the federal government in the litigation and no payment was made to the federal government of Nigeria itself.

According to the cable, Liggeri also told U.S. officials that the lawsuits were “wholly political in nature,” and that the humanitarian group Doctors Without Borders also gave children Trovan. Officials with the organization said that is not the case, and other records suggest that only Pfizer would have had access to Trovan at the time.

Doctors Without Borders published this response in 2011: “Among the US government diplomatic cables recently published by the Wikileaks website were details of a meeting between an official from the pharmaceutical company, Pfizer, and US Embassy officials in Nigeria in April 2009.

At the time of the meeting, Pfizer was in the midst of a legal battle with Nigerian government officials regarding a medically unethical antibiotic clinical trial in children. The clinical trial took place in Kano State in 1996 during a massive meningitis outbreak.

Pfizer carried out the trial of the oral antibiotic trovafloxacin, branded Trovan, even though there had not been any previous medical evidence that it could be effective against meningitis. The Pfizer researchers conducted the trial in Kano State Hospital, where a Doctors Without Borders/Médecins Sans Frontières (MSF) team was treating children using a preferred and clinically approved antibiotic regimen for bacterial meningitis.

A US$75 million settlement with the State of Kano was reached July 30, 2009. Other cases are still pending before the US courts and the Nigerian federal government continues to pursue legal claims against Pfizer.

It is against this backdrop that Pfizer falsely accused MSF in the US diplomatic cables of using Trovan. Documented evidence has shown that these accusations are patently false. MSF did not, at any time, administer Trovan to patients. Litigation connected to this case and comprehensive investigative reports on the matter suggest that Pfizer’s attempts to rewrite history are intended to deflect responsibility for the company’s actions.

MSF was not working in the same part of the hospital in Kano State as Pfizer clinical researchers, and MSF staff had no connection to Pfizer. When MSF staff became aware of what Pfizer was doing, they were appalled at the practices of the company?s team. MSF personnel on the ground communicated their concerns to both Pfizer and the local authorities.

“It was not a time for a drug trial,” says Jean Hervé Bradol, former president of MSF France, to whom the Kano teams were reporting at the time. “They were panicking in the hospital, overrun by critically ill patients. The team were shocked that Pfizer continued the so-called scientific work in the middle of hell.”

Pfizer officials have made no attempt to clear the record as of yet and retract these unsubstantiated claims against MSF. A handful of internet reports have adopted the version of events proffered by the Pfizer official.

An exhaustive Washington Post investigation, drawing on extensive background information and interviews provided by MSF staff, published on December 17, 2000, makes clear the distinction between Pfizer?s activities and the work of MSF during the meningitis outbreak:

‘Behind a gate besieged by suffering crowds stood two very different clinics. A humanitarian charity, Doctors Without Borders, had erected a treatment center solely in an effort to save lives. Researchers for Pfizer Inc., a huge American drug company, had set up a second center. They were using Nigeria’s meningitis epidemic to conduct experiments on children with what Pfizer believed was a promising new antibiotic?a drug not yet approved in the United States.’

The article later triggered the various legal proceeding taken by the victims and Nigerian authorities against Pfizer.

With proven treatments at hand, Pfizer instead chose to carry out tests for an unproven drug on children whose lives hung in the balance. ‘The situation called for using treatment protocols known to be effective rather than carrying out clinical trials on a new antibiotic, with uncertain results,’ said Dr. Bradol.”


BBC reported it too at the time (2010):

“According to a US cable released by WikiLeaks, Pfizer wanted to “put pressure” on Michael Aondoakaa. He was heading a lawsuit against the company over a 1996 drug trial during a meningitis epidemic.
The trial allegedly led to the deaths of 11 children – charges Pfizer denies.
Pfizer reached a $75m settlement last year with Nigeria’s Kano government over the case, which also allegedly left dozens of children disabled.

In a statement released by Pfizer in response to the leaked diplomatic cable published by the UK’s Guardian newspaper, the pharmaceutical company said it “negotiated the settlement with the federal government of Nigeria in good faith and its conduct in reaching that agreement was proper”.

The cable quoted conversations said to have taken place between US embassy staff and Pfizer’s head in Nigeria, Enrico Liggeri. It referred to a meeting between Mr Liggeri and US officials on 9 April 2009.

“According to Liggeri, Pfizer had hired investigators to uncover corruption links to Federal Attorney General Michael Aondoakaa to expose him and put pressure on him to drop the federal cases,” the cable released by the whistle-blowing website WikiLeaks said. “He said Pfizer’s investigators were passing this information to local media.”

Mr Aondoakaa was removed from the position of justice minister in February this year by Nigerian President Goodluck Jonathan.”

Thing is no one has ever proven a Wikilieaks cable to be fake, definitely not this one.

Another good report on the cables I found in mainstream-media comes from the Atlantic (2010):

“In 2000, following the Post revelations, a cry for justice in the Nigerian media triggered street protests and an investigation by Nigeria’s health ministry, whose report on the incident went missing until 2006, when a leaked version revealed that the health officials had reached more or less the same verdict as the fired Pfizer expert: The experiment was “an illegal trial of an unregistered drug,” a “clear case of exploitation of the ignorant,” and a violation of Nigerian and international law.

These disclosures prompted a raft of civil and criminal lawsuits in Kano State Court on behalf of the families and in Federal High Court on behalf of the nation itself, as it were. But Pfizer kept the suits tangled up in proceedings to postpone any settlement.

A State Department cable dated April 20, 2009 and released by WikiLeaks, however, suggests that Pfizer’s legal strategy was not simply to delay–it was also to blackmail. Written by an economic counselor at the US embassy in Abuja, Nigeria, the cable reports minutes of meetings during which Pfizer representatives informed the U.S. ambassador that the firm had agreed to settle the Kano State suit for $75 million, mere pocket change for the pharma giant. The ambassador was told that Pfizer “was not happy settling the case, but had come to the conclusion that the $75 million figure was reasonable because the suits had been ongoing for many years costing Pfizer more than $15 million a year in legal and investigative fees.”

It was how Pfizer deployed these fees that dropped a bombshell:

According to [Pfizer country manager Enrico] Liggeri, Pfizer had hired investigators to uncover corruption links to Federal Attorney General Michael Aondoakaa to expose him and put pressure on him to drop the federal cases. He said Pfizer’s investigators were passing this information to local media, XXXXXXXXXXXX. A series of damaging articles detailing Aondoakaa’s ‘alleged’ corruption ties were published in February and March. Liggeri contended that Pfizer had much more damaging information on Aondoakaa and that Aondoakaa’s cronies were pressuring him to drop the suit for fear of further negative articles.

Blessed with immense reserves of oil, Nigeria, like many oil-rich developing nations, has in turn been cursed with extravagant corruption. Aondoakaa was among those caught up in it. The cable does not mention Pfizer’s settlement of the $6 billion federal lawsuit, which was signed in secret by lawyers from Pfizer and the Aondoakaa-led Nigerian ministry of justice in October 2009. With the settlement’s terms under wraps, how much Pfizer paid and to whom remains a mystery.

In February 2010, Aondoakaa was booted from the government over charges of corruption. Pfizer denies the version of events reported by the U.S. Department of State official. “Any notion that the company hired investigators in connection to the former attorney general is simply preposterous,” Christopher Loder, a Pfizer spokesman, told The New York Times.

When I emailed Loder asking for comment about the allegations in the WikiLeaks cables, he repeated his statement to the Times verbatim, adding that the cases had been “resolved in 2009 by mutual agreement” and that Pfizer’s conduct was “proper.”

The 1996 Trovan tragedy has cast a long shadow. In 2003, the parents of Kano State boycotted a U.S.-made polio vaccine, threatening to single-handedly short-circuit the global initiative to eradicate the disease. These parents bore the legacy of the Trovan trial and the ensuing years of failed and foiled litigation. Suspicion and cynicism of Western motives ran so deep that they accepted their local clerics’ warnings that the polio vaccine was a plot by Christians to sterilize their daughters, relenting only when health officials switched to a vaccine manufacturer based in Indonesia, a Muslim nation.

Despite all this, Pfizer apparently perceives itself as the real victim. As detailed in the leaked cable, Liggeri portrayed Pfizer to the ambassador as entirely the injured party, dismissing the lawsuits as “wholly political in nature” and asserting that during the meningitis outbreak in 1996, MSF also administered Trovan to children. (When asked for comment by the Guardian, Jean-Hervé Bradol, former president of MSF France, said, “We have never worked with this family of antibiotic. We don’t use it for meningitis. That is the reason why we were shocked to see this trial in the hospital.”) Liggeri warned darkly that the lawsuit against Pfizer had so chilled the entire pharmaceutical industry that “when another outbreak occurs no company will come to Nigeria’s aid.” Whether or not that’s true, it’s not clear that Nigerians would want Pfizer’s help after all.”

However, it took some real alternative independent media to reveal the gravity of the situation, in 2010, when the Democracy Now! news outlet hosted an Washington Post reporter involved in the case and a Nigerian journalist. Dhe deadliest details came together:

“After our stories, there was an official federal investigation in Nigeria. But it was never made public. It disappeared. And many years later, we finally got a copy of this report. It concluded that Pfizer had violated both Nigerian law and international law and was very critical. It also mentioned that members of the investigative panel had been the target of death threats during their investigation. We were told there were three copies of this report. Attorneys in the U.S. who brought a class action lawsuit said they had spent years trying to find this report that we came up with. One they tracked to a safe. And when they opened the safe, it was not there. Another was supposedly in the possession of a man who died before lawyers got to him.
After we made this report public, there was a new set of public officials in power in Nigeria, and they decided to bring criminal and civil charges against Pfizer, including homicide — both Pfizer and some current and former employees of Pfizer. The state of Kano in the northern Nigeria settled for $75 million. The federal charges, which initially were seeking $7 billion from Pfizer, just sort of evaporated. We never knew what happened to them. And now, this new revelation comes out and raises very serious questions about why those charges just evaporated.” – Joe Stephens is a staff writer for the Washington Post. He was part of the investigative team that broke the story in 2000

Musikilu Mojeed, a Nigerian journalist  who has worked on this story for the NEXT newspaper in Lagos, commented the following: 
“Nigerians are clearly outraged by this revelation that Pfizer hired investigators to smear the attorney general, to blackmail him to drop the federal charges. But not a lot of people are entirely surprised in Nigeria, because before the WikiLeaks cable came out, our newspaper, NEXT, had exposed the mysterious disappearance of the federal charges against Pfizer. You know, suddenly, the case just disappeared. Nobody knew how the case was withdrawn. Nigerians were not told. It was just done in secret. And our newspaper broke this story. That is, a $6 billion federal suit against Pfizer disappeared secretly, that the attorney general simply did — went into a secret deal with Pfizer and a few Nigerian lawyers without anybody knowing about it. In fact, Pfizer may have violated U.S. law, because Pfizer refused to disclose the details of that settlement, even in its filing for the quarter of 2009 to the U.S. government. So, Nigerians are clearly outraged.

And even the attorney general, the former attorney general, himself, is threatening that he might sue Pfizer for blackmailing him. But in any case, the attorney general himself is known to be terribly corrupt. So a lot of people are not surprised, because he’s know to be a corrupt man. He cannot enter the United States, because the U.S. government has barred him, has withdrawn his visa and that of his family, because he’s known to be corrupt. But a lot of people are outraged that Pfizer could go to that extent to hire an investigator to blackmail a Nigerian official.”

Evidences of various forms of wrong-doing on the Pfizer side kept appearing the following years, see this 2011 CBS news piece:

Pfizer Bribed Nigerian Officials in Fatal Drug Trial, Ex-Employee Claims

“A former Pfizer (PFE) employee’s letter to a federal judge alleging that the company put a courier on a KLM flight to Nigeria carrying bribes for local officials is a classic example of how hard it is to get away with corporate skullduggery: The letter cites 40 Pfizer executives, FDA officials and other witnesses who allegedly have inside knowledge of the scandal — not very secret for a secret conspiracy.(…)

The letter was written by Dr. Juan Walterspiel, who in 1996 was a pediatric research physician in Pfizer’s Groton, Conn., facility. He worked on the Trovan trials, but he objected to the testing method being used. Pfizer dismissed him in 1998. His letter claims that:

  • Pfizer paid a bribe to continue the study of Trovan.
  • Pfizer did not get informed consent from parents of children in the test.
  • Pfizer gave fake ethics documents backing the test to the FDA.
  • Corners were cut because “Speed was of the essence and stock options and bonuses at stake.”
    Pfizer ignored Trovan’s poential reaction with antacids, which are often given to patients who have had surgery.
  • The FDA started but mysteriously called off an investigation into the scandal.
  • One patient in the Trovan arm of the experiment died without being taken off Torvan or given medical care. Normally, if patients react badly to experimental drugs researchers take them off the therapy and give them medical care.
  • Pfizer has photographs of the members of its Kano team.

The letter was previously dismissed in a previous ruling in the case as “speculative” and too filled with hearsay to be regarded as evidence. Pfizer told BNET:

Dr. Juan Walterspiel’s employment with Pfizer was terminated in 1998 for legitimate and proper reasons. Dr. Walterspiel did not travel to Nigeria to participate in the 1996 Trovan clinical trial and thus has no direct or first-hand knowledge of the conduct of the clinical trial. Dr. Walterspiel made these similar allegations over 10 years ago, and has repeated them from time to time since then. Pfizer investigated the allegations and found that they were not supported by the facts.”

Walterspiel’s letter was based on an affidavit filed in the case in the early 2000s. At the time, much of the case was under seal and documents were not electronically filed, so Walterspeil’s allegations went largely unnoticed beyond the lawyers who saw them. Walterspiel then wrote to former Pfizer CEO Jeff Kindler in 2007, repeating his claims. He sent a copy of that letter it to Judge William Pauley on Jan. 28, 2011, who entered it onto the record a few days ago.

The letter does not name names. Instead, Walterspeil uses numbers to stand in for the identities of the people he links to the Trovan trial. Three of them knew that Pfizer had sent a cash courier to some Nigerian officials who “needed to be paid off” before the trial could continue.
Pfizer had not obtained the proper ethics committee approvals before the test began, Walterspeigel claims. (Research on human subjects usually requires approval of an independent institutional review board before it can start.) So the paperwork was faked.
The FDA began investigating the Trovan trial but the probe was suddenly ended.
The older ruling supplies some of the names behind the numbers. Local sources also accused corruption between the corporation and the government.”

In addition to blaming Pfizer, many local media commentators also lamented what they saw as a corrupt Nigerian administration that had rubber-stamped the trial without due diligence. “The propensity for corrupt practices on the part of a few venal Nigerians has apparently permitted our people to be used as a laboratory for the unregulated testing of a new drug with obviously bad consequences thereof,” read a Feb. 8 editorial in Lagos’s independent weekly Tempo.

Meanwhile, the residents of Kano have been left with a legacy of fear. The News, a weekly magazine from Lagos, reported on Jan. 29, 2001 that people in the district are refusing new immunizations for CSM, cholera, and measles. “The bature (white men) will kill us again if we allow them to give us…tablets and injections,” they told the magazine.

According to John Murphy’s report for the Baltimore Sun, the Trovan trial may have left some Nigerians distrustful of Western interventions: “Some of Kano’s fears of the vaccine stem from its experience with the U.S. pharmaceutical giant Pfizer Inc.”

“The country’s health authorities say that the Pfizer controversy is partly responsible for many families in northern Nigeria refusing to allow their children to be vaccinated against polio. That in turn has been blamed for an outbreak that spread across parts of Africa. The Kano authorities also refused to distribute the polio vaccine.” – The Guardian 2007

Epilogues:

1

2. Meet Nigerian born Dr Onyeama Ogbuagu, who is allegedly at the core of developing the Pfizer vaccine. He is one of the twin sons of Prof. Chibuzo Ogbuagu. His parents had the twins in New Haven CT when they went for their doctoral programs at Yale. The Ogbuagu’s returned to Nigeria where Onyeama studied medicine and then returned to the US and Yale.


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! Articles can always be subject of later editing as a way of perfecting them