Tuesday, October 11, 2016

Alnylam Pharmaceuticals: RNAi Failure Could Catch Monsanto Investors Off Guard ?

Jose A. Bernat Bacete/Getty Images

Common white button mushroom (Agaricus bisporus)
has been modified to resist browning.
Anyone Remember this article from the journal Nature ?
The article wasn't so much about how a fungus engineered with the CRISPR–Cas9 technique can now be cultivated as it was about the government allowing Biotechs to market their wares to be sold without any further regulation or oversight. 
“The research community will be very happy with the news,” says Caixia Gao, a plant biologist at the Chinese Academy of Sciences’s Institute of Genetics and Developmental Biology in Beijing, who was not involved in developing the mushroom. “I am confident we'll see more gene-edited crops falling outside of regulatory authority.”  
"The United States is revamping its rules for regulating GMOs, which collectively are known as the Coordinated Framework for Regulation of Biotechnology. To that end, the US National Academies of Sciences, Engineering and Medicine have convened a committee that is charged with predicting what advances will be made in biotechnology products over the next 5–10 years. It will hold its first meeting on 18 April.
Nature.com: "Gene-edited CRISPR mushroom escapes US regulation"
Image - Alejandra Pales/Flickr
I touched on this same subject [gene editing, CRISPR, RNA interference, Arctic Apples etc] recently where a newer variety of apple [Arctic Granny Smith] will be introduced with the same CRISPR gene deletion or silencing technology and get that precious get out of jail free card, Pass Go and collect $200. Figuratively speaking of course. This technology being used in the apples is where the gene for the production of the very important immune system enzyme Polyphenol Oxidase [which also causes browning] is being silenced so that people can add another "White" marketed product to their daily modern diet. As you are aware, in our perverted warped modern enlightened world, white has always been promoted superior to anything brown in a number of ways. Yes, flour, sugar, potatoes, apples, etc we are told are superior quality if they are white. Unfortunately this bigotted view between brown and preference for white has it's roots dating back over 150 years ago during the Victorian Era and it's infected everything else humans have done since then. Without restating much more about what was written regarding Arctic Apples, this is what I wrote last week about the immune system importance of Polyphenol Oxodase. Not only for us and other living things, but also for the apple tree's immune system, which if hindered or not functioning properly requires more science-based synthetic pesticides:
CRISPR: The kinder, safer, risk-proof version of GMO ?
But the really important point to take note of here is the Biotechs once again establishing & dictating to the authorities just what the regulations or lack of laws and regulations will be with CRISPR Cas9 gene editing and RNAi technology. They are promoting this as fool proof or failsafe compared to earlier GMO technology. So much so that they wish to rename the technology and dump the term GMO. Something has happened recently which exposes the real dangers of even this technology irrespective of the proponent's  advertising it as safe. What I find interesting is that this news has to come from Financial and other online business journals as opposed to Science journals and other research publications which should have jumped on this first. The other technology besides CRISPR gene editing, which is the subject of this post is called RNAi technology. See link in references below as to the differences between CRISPR & RNAi technologies.

image - wholetrades.com
Investors often associate biotech with healthcare, but biological technologies are applied across unrelated industries. This biopharma failure could have consequences for next-generation agricultural products from companies like Monsanto and Intrexon(of Arctic Apple fame)  - Motley Fool
Alarm Bells went off in the financial world just recently where a major failure has taken place in this RNAi technology and some people died as a result. Most investors are ignorant when it comes to understanding what the positives & negatives will be with the biotechnology industry and their inventment in them. Hence they rely on a stock broker hucksters to provide them the latest pitch from any Biotech public relations which promise fortunes to be made if they pour their money into A,B or C Biotech company. The investors are advised by their brokers that, "Hey, Biotechs are the new future. If I were you, I'd place a bet on Blue Note"(remember  movie, "The Sting"?)  Except when an inconvenient bomb shell truth comes along and ruins everyone's Wall Street day. 
On Wednesday evening Alnylam Pharmaceuticals (NASDAQ:ALNY), a leading developer of RNAi drugs, announced that it had decided to discontinue the development of revusiran, its lead drug candidate, after an "imbalance" of deaths for patients receiving the experimental drug compared to placebo.
So something went horribly wrong, they don't really know what it was other than it failed, caused death of some patients and so they discontinued the experimental drug. This has an uncanny similarity to and is reminiscent of the Tryptophan disaster - GM Potato & Árpád Pusztai affair & the GM pea causes allergic reactions to name a few. Admittedly, these examples were transgenic in nature where a single foreign gene was taken from one organism and inserted into another entirely different organism. Bottomline though is they do not totally understand genetic information. So the original biotechnology way of doing things had problems. In the case of the Showa Denko, Tryptophan incident where 37 people died and 1,500 were permanantly disabled from 1989 to 1991, we'll never know the true reasons of what went wrong because Showa Denko ordered their staff to destroy all sampling and sanitized the lab. They then further concocted a phony cupcake story of it being a problem of the weaker charcoal filters they used which later turned out to be a fabricated lie exposed by a lawyer in the case who revealed that 100s of the mishaps were prior to this supposed change in filters. The two other examples also gave clues as to what went wrong. First the Australian researchers who took the bean gene for a protein capable of killing the pea weevil pests and transferred it into the pea. When extracted from the bean, this protein did not cause any allergic reactions in mice or people. However, this team found that when the bean gene for the manufacture of this protein is  epigenetically expressed within the pea genome, its structure is subtly different to the original structure within the bean. They concluded that this structural change could be to blame for the unexpected immune effects seen in the lab mice. Oddly enough this was the exact same observation and conclusion Dr Arpad Pusztai's own studies showed that purified Lectin from the Snowdrop plant wasn't toxic to rats. There are numerous forms of Lectin all of which help the immune systems of many organisms. This is why this particular form of Lectin from the Snowdrop plant was chosen  because of it's ability to disrupt the intestinal lining of the pest insects. The problem was when the gene was introduced into the genome of the potato, the instructions from the gene didn't jive with the new foreign instructions within the context of the new genes it would then be working with in a foreign organism (potato). What the researchers were ignorant of was the consequences for potential harmful epigenetic gene expression, much like that of the Bean protein gene inserted into the pea. 

This is certainly interesting and it appears biotechs have recognized this for a longer time than they'll admit. For example, it is fortunate for all of us that with the Bean/Pea study, that this was a publicly funded project or the results would have been shelved and locked away never to see the light of day. Being publicly funded, they were accountable to the public. One wonders how many other horror stories that may exist in the X-Files of Biotech basements around the globe. However, RNAi (RNA interference), like CRISPR was supposed to eliminate all those fears as it has been hailed as a more accurate precise sure-fire failsafe method where nothing can go wrong. Hence, the spin that no regulation is needed. One of the other major problems with the technicians using the earlier agro-bacterium was the random nature of where the gene ended up in the target organism's genome. This newer CRISPR Cas9 Technology has been developed with the  intent to target GM gene insertion or deletion to a predetermined site within the plant’s DNA in an effort to obtain a more predictable outcome and avoid the complications that can arise from random insertional mutagenesis. But take a look at some of the admitted challenges referenced in the same Motley Fool investors article with this new RNAi technology under this subheading:
Nobel Prize hype, real-world difficulty
What exactly is RNAi, anyway? RNAi stands for "RNA interference," a natural process that has shown promise in regulating gene expression in humans, plants, and other organisms in a controlled setting. In biopharma, researchers are exploring its ability to "turn off" or "turn down" the production of misfolded proteins that cause disease. In agricultural biotech, researchers have used the same technique in the lab to engineer better seed varieties: Monsanto has enhanced the oil profiles of soybeans, while Intrexon has made non-browning apples by reducing the amount of a protein that oxidizes (and turns the apple brown) when exposed to air.    
Researchers can target protein production with RNAi by knowing the sequence of the gene in question. But therein lies the problem: Two or more genes can have long stretches of similar sequences. That's a problem if, say, a disease-causing gene a compound is targeting shares a sequence with a gene essential to survival. A single off-target effect could have devastating -- even fatal -- consequences. 
 RNAi Pitfalls extend beyond Biopharma
But both Monsanto and Intrexon are looking to exploit the potential of RNAi technology in the field. It's difficult enough to minimize off-target effects and find the optimal delivery mechanism within the human body. Not to downplay the complexity of biology and human physiology, but these obstacles become orders of magnitude more difficult when the technology is released into the environment.   
In theory, RNAi represents a better approach to fighting agricultural pests than the current available solutions do. While pesticides can sometimes indiscriminately eliminate pests and other organisms caught in the crossfire, a highly specific RNAi product could eliminate only pests and have no effect on other organisms. Can these companies be sure that RNAi doesn't accidentally target one of the other hundreds of organisms in the field? It will be difficult to answer this question with absolute certainty, and the risks might outweigh the rewards.  
(Source - Motley Fool)

There's clearly something fishy here with the ongoing Biotech smokescreening of potential for harm, but why would Scientists themselves with any sense of bioethics be hiding any negative data which would help expose the potential for harm to human & natural world health ?
Another recent article from yet another financial publication reveals what actually goes on in the corporate industrial world behind closed doors. The article illustrates the biases and motives behind a plethora of published possitive results for proving many hypothesis today which can mean financial fortunes.
Investors Buriness Daily: "Is Modern Science Polluted?"
"For years, scientists and non-scientists alike have complained that something is fundamentally wrong with the way we do this business. Something has corrupted the integrity of our science."   
"The things that scientists crave -- like tenure and research funding -- incentivize frequent publishing of massive numbers of academic papers. To publish that much, you need a tremendous amount of financial support.  And when it comes to scientific work that could have regulatory implications, almost all of the money comes from Washington."  
So we now get a sense here that motivation has everything to do with this need for positive results. Take note below why:
"What constitutes "bad science"?  It's the epidemic of positive results, in which a researcher reports that the data support his or her prior hypothesis.  Stanford's Daniele Fanelli has shown a distressing increase of positive results in recent decades, something that can't be true in the real world.  Think about it -- we are not suddenly becoming more intelligent and getting everything right. What's happening is that scientists are responding to incentives." 
"Usually, hypotheses are put forward in some grant proposal.  Financial backers don't like negative findings, because negative findings don't support the work that they've funded. Supervisors lose face and researchers can lose their funding."
So financial incentives for company managers and pressure from investors tend to hurry up results. Therefore embellishing, exaggerating and leaving out the negative findings are the norm in published results for obtaining investor interest or government grants or the funding dries up. Still, I found it odd in the beginning  that it was only the financial sector journals which broke this news story and not science publications. Since then after this story first broke, the science online journal Nature has published an article on this subject.
Chart from Nature.com

Nature.com: Investors flee as firm scraps RNA-interference drug candidate 
Struggling RNAi field faces another blow as its first treatments near the clinic 
But investors are worried about more than just the loss of one experimental drug, says analyst Alan Carr of the investment bank Needham & Company in New York City.  
“They’re concerned that this safety signal may be an issue for the rest of the platform,” he says. “That’s why we’ve had such a strong reaction.”    
And revusiran, Carr notes, used an older technology to stabilize the RNA in the body. As a result, it required higher and more frequent doses than would many of Alnylam’s newer drug candidates. “My view is that this reaction is overblown,” Alan Carr says. “But at this point, I’m obviously in the minority.”
Yes, but of course as Alan Carr says, the overblown reaction is just his opinion. So what about RNAi technologies, the Biotechs and the lack of regulation ? Back in 2013 & 2015 this subject (RNA based insecticidal soaps and sprays) was being discussed and debated. Monsanto was adamant that no regulation or rules on the subject were necessary. An article published in Technology Review by MIT Technology Review Editor, Antonio Regalado, had this to say about how the rules or no oversight would be set up by the FDA according to Monsanto:
"Deep inside its labs, Monsanto is learning how to modify crops by spraying them with RNA rather than tinkering with their genes"
"Monsanto has been laying groundwork for the inevitable safety debate. It sent staffers to grocery stores and farm stands to collect fruits and vegetables that appeared to be suffering from viral infections. Analyzing these, they found thousands of fragments of viral RNA, many of which closely matched human genes. Yet it’s not known that anyone has been harmed by RNA in produce. Given this “history of safe consumption,” the company concluded, mere matches between RNA triggers and human genes have “little biological relevance.”   
"Last year the U.S. Environmental Protection Agency asked a panel of experts to help it decide how to regulate RNA insecticides, including sprays as well as those incorporated into a plant’s genes. In an 81-page letter to the agency, Monsanto lobbied against any special rules. It said RNA products should actually be spared safety tests it called irrelevant, including those designed to assess whether they were toxic to rodents and whether they could cause allergies, as well as in-depth studies of what happens to the molecules in the environment. Only proteins cause allergies, Monsanto said. And when the company doused dirt with RNA, it degraded and was undetectable after 48 hours."
Technology Review - Biomedicine: The Next Great GMO Debate
If you've ever watched the documentary, "The World According to Monsanto," then you know at the very beginning how they helped dictate to the US Government just how their GMO technology should be regulated. Remember, their argument was that they are only using genes or DNA and everything humans eat has genes or DNA in it, so GMO technology should not have the same regulation as food additives. Many of the heavy hitter supporters and promoters like Robb Fraley & Alison Van Eenennaam used the same simplistic illustration in justifying gmo technologies. Genes are just genes and DNA is just DNA, what's the big deal. You take one gene from here and put it with other genes there. The description was always a dumb comparison to kid's Lego toys or Tinker Toys. No, the problem is both DNA and RNA are information. And that's where the problem comes in. Many scientists have hang ups about information being real intelligent complex sophisticated information. To many it's just nothing more than patterns of chemical molecules which just happen to accomplish some things. The facts are, they do not fully understand the informational content of DNA or even RNA. We are reading all the time where new discoveries are shedding light on the functionality of non-coding DNA. This was formerly labeled "Junk DNA" because these intellectuals had no clue decades ago what the non-coding genes did, hence they blindly asserted that these genes must be worthless junk left over from some evolutionary mistakes of the past. Now things have changed radically. They are finding that some genes have multiple layers of codes, codes within codes. The fact is, these people are incapable of admitting to the public that they really may not know everything and that would be bad business. There isn't a human alive who can accurately translate all the genetic information into understandable human language for better understanding. They are light years from that. I've given this illustration before. If we were to observe a pattern of Arabic &/or Chinese characters, does it mean that there is no real informational content there if we do not write, read or speak either of those languages ? Take a look:
ما هو تعريف المعلومات كلمة؟  or  信息的定義是什麼
Do you know what both lines of characters say ? Do a google translate, it asks the question, "What is the definition of information?" What now if the genetic code was actually an unknowable extraterrestrial language from outside of our solar system ? Because it was impossible to decifer, does that mean there is no real meaningful information in the genetic code ? The insaneness of some of the excuses and justifications here regarding no supervisional oversight or regulation on RNAi technology is asinine. It's clear from the mistakes above that they really do not know and fully understand everything there is to know about how the genetic code works and our increase understanding of epigenetic gene expression is proving that every single day. This has always been about corporate business interests first, with science being used as a crutch to lean on. The potential for serious problems regarding concerns about safety go way back with regards this RNAi technology which has actually been used in the past. I'll list them below.
Concerns over RNAi Technology not new
RNAi-Based Insecticidal Crops: Potential Effects on Nontarget Species
USDA researchers confirm Heinemann conclusions on RNA-interference risks
Dr Jonathan Lundgren, RE: Complaint of Violations of USDA Scientific Integrity Policy
So what's the differences between CRISPR & RNAi technologies ?
Genetic Engineering & Biotechnology News: Advertorial: Comparing RNAi and CRISPR Technology for Loss-of-Function Genetic Screens
What are the differences between gene knockout by CRISPR and by RNAi?
 Get Well in the RNAi Way-RNAi, A Billion Dollar Baby in Therapy
Important References to material above
Showa Denko Tryptophan Incident

World Renowed Scientist, Árpád Pusztai, loses job over GM Potato Warning

New Scientist: GM pea causes allergic damage in mice

What is the principle of "substantial equivalence" ???
Well, now you know why the article title in Motley Fool provided a warning shot across the bows of Monsanto and other biotechs who are pushing for unrestricted freedom. Now that Bayer has bought Monsanto and they want to change the name. You should also know that they also want to change the name of this technology to not reflect the initials GMO. See, GMO leaves a bad taste in folk's mouths. It's a P.R. marketing stunt. The problem is it is still genetic manipulation. Given that they have attempted to definition shell game what genetic modification means (equating traditional animal and plant breeding with Lab coats genetic manipulation as the same), why should people allow them to game the subject again and smokescreen another technique ? Think about it and if you have time read this on that very thing:

CRISPR and the Monsanto Problem (GMO, be some other name!)


  1. See also: Get Well in the RNAi Way-RNAi, A Billion Dollar Baby in Therapy http://www.omicsgroup.org/journals/get-well-in-the-rnai-wayrnai-a-billion-dollar-baby-in-therapy-2168-9547-1000158.php?aid=68985

  2. See also: RNA-Guided Human Genome Engineering http://www.freepatentsonline.com/y2016/0002670.html

    Excerpt: "Repetitive elements or endogenous viral elements can be targeted with engineered Cas+gRNA systems in microbes, plants, animals, or human cells to reduce deleterious transposition or to aid in sequencing or other analytic genomic/transcriptomic/proteomic/diagnostic tools (in which nearly identical copies can be problematic)."

    The idea that this technology could use a virus to biophysically constrain the virus-driven energy theft that has been linked to all pathology seems absurd. Calling it "RNA-guided" instead of RNA-mediated focuses on treatment instead of prevention via what is known about RNA-mediated autophagy and energy-dependent chromosomal rearrangements that biophysically constrain virus-driven pathology.

    1. Viruses are gefinitely becoming more and more interesting. Take this article from Atlantic on Black Widow gene stolen by virus for a purpose.

      The Virus With Spider DNA


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