DNA and RNA

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Tero
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Re: DNA and RNA

Post by Tero » Mon Dec 28, 2020 8:34 pm

I used to make nucleosides, the pieces without the phosphate part. I had never seen that, though we changed every part of the sugar and heterocycle to see what the effect was. I collected a report of nucleosides that are substrates for kinases for the boss. Not every nucleoside you can imagine is entered into the natural system of pathways. I correctly predicted that we should make the cytidine analog of things we made. Only the sugar (ribose) parts was changed. Our competition already made one:
https://en.wikipedia.org/wiki/Gemcitabine
it became a cancer drug.

I used to go to conferences where both nucleosides and nucleotides were discussed. Man made nucleotides like the psudouridine were incorporated into DNA bits they made. The trouble back then, 1980-1990, was that injectable drugs were not in favor. So they got nothing past animal studies. There was a big effort to make so called "antisense nucleotides."

Now that we are addressing viral diseases and cancer, it is worth noting that proteins are routinely given by injection, like humira. So there is no longer a hurdle to people wearing some device that slowly feeds the injectable drug into the body.

The future of drugs is in these, and it will be costly. Biochemicals such as these are a great effort to make, compared to our old time "pills."
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Re: DNA and RNA

Post by NineBerry » Mon Dec 28, 2020 8:35 pm

Everything gets cheaper once you start producing more of them. Think about how cheap smartphones are today.

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Re: DNA and RNA

Post by Tero » Mon Dec 28, 2020 8:47 pm

NineBerry wrote:
Mon Dec 28, 2020 8:35 pm
Everything gets cheaper once you start producing more of them. Think about how cheap smartphones are today.
The cheapness in these is labeled "biosimilar,"

https://www.tevabiosimilars.com/?utm_so ... lsrc=aw.ds

Once the patent runs off in humira, these biosimilars will enter the market. They will differ from the innovator drug slightly, just by the technology used to make them.

In the case of RNA or DNA there will also be "trade secrets" that are not patented. You only need to claim the RNA or DNA part with its modified DNA bits to get the patent. You do not need to disclose additives that make your drug stable.

Or you list about 50 additives in your patent claim and say that they all work. You don't say which one is in your drug. You give the FDA the recipe but they do not publish it.

These RNA and DNA wizzards were thought of as dreamers in the 90s because "how would you get it in the cell?"
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Re: DNA and RNA

Post by Tero » Mon Dec 28, 2020 9:35 pm

The uridine analog notated with psi is a natural nucleoside and has certain properties:
https://en.wikipedia.org/wiki/Pseudouridine
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Re: DNA and RNA

Post by Tero » Tue Jan 12, 2021 4:15 pm

https://esapolitics.blogspot.com

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Re: DNA and RNA

Post by NineBerry » Fri Jan 29, 2021 3:23 pm


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Re: DNA and RNA

Post by Tero » Fri Jan 29, 2021 8:48 pm

NineBerry wrote:
Fri Jan 29, 2021 3:23 pm
Video of someone doing the science

https://twitter.com/AdamRutherford/stat ... 01088?s=19
I tried to teach many chemists how to cut glass. It was needed for TLC (silica) plates. None ever learned. They all ruined the glass cutter in a day. I would use the same one (hidden from them) 5-10 years.
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Re: DNA and RNA

Post by NineBerry » Fri Jan 29, 2021 8:54 pm

Tero wrote:
Fri Jan 29, 2021 8:48 pm
NineBerry wrote:
Fri Jan 29, 2021 3:23 pm
Video of someone doing the science

https://twitter.com/AdamRutherford/stat ... 01088?s=19
I tried to teach many chemists how to cut glass. It was needed for TLC (silica) plates. None ever learned. They all ruined the glass cutter in a day. I would use the same one (hidden from them) 5-10 years.
How many of them went on to become Prime Minister?

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Re: DNA and RNA

Post by Tero » Fri Jan 29, 2021 9:12 pm

NineBerry wrote:
Fri Jan 29, 2021 8:54 pm
Tero wrote:
Fri Jan 29, 2021 8:48 pm
NineBerry wrote:
Fri Jan 29, 2021 3:23 pm
Video of someone doing the science

https://twitter.com/AdamRutherford/stat ... 01088?s=19
I tried to teach many chemists how to cut glass. It was needed for TLC (silica) plates. None ever learned. They all ruined the glass cutter in a day. I would use the same one (hidden from them) 5-10 years.
How many of them went on to become Prime Minister?
I had one assistant that went on to be a pharmacist. Is that good enough? He worked for me for half a year. In that time he got his pharmacy credentials from India and spoken English test passed. He was below average in lab skills and had to be checked on every 45 min. It was a good thing he went to a field with less glassware.
https://esapolitics.blogspot.com

If you don't eat your meat, you can't have any pudding!
How can you have any pudding if you don't eat your meat?
You! Yes! You behind the bike sheds! Stand still, laddie!

Dominus vo-bisque'em Et cum spear a tu-tu, oh!

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Re: DNA and RNA

Post by Tero » Fri Jan 29, 2021 9:31 pm

7523998B-177D-41FF-9C7E-F8E44718DDA8.gif
7523998B-177D-41FF-9C7E-F8E44718DDA8.gif (24.51 KiB) Viewed 862 times
Professor Boris is pipetting. I never used an Eppendorf pipette, more of a biochemist tool. I used, as do synthetic chemists now, syringes. I used glass, plastic syringes are used a lot. But you end up cleaning them anyway, before disposing.
https://esapolitics.blogspot.com

If you don't eat your meat, you can't have any pudding!
How can you have any pudding if you don't eat your meat?
You! Yes! You behind the bike sheds! Stand still, laddie!

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Re: DNA and RNA

Post by Tero » Sat Feb 06, 2021 3:51 pm

Scientists at Moderna, a biotech specializing in messenger RNA, were able to design a vaccine on paper in 48 hours, 11 days before the US even had its first recorded case. Inside of six weeks, Moderna had chilled doses ready for tests in animals.

Unlike most biotech drugs, RNA is not made in fermenters or living cells—it’s produced inside plastic bags of chemicals and enzymes. Because there’s never been a messenger RNA drug on the market before, there was no factory to commandeer and no supply chain to call on.

When I spoke to Moderna CEO Stéphane Bancel in December, just before the US Food and Drug Administration authorized his company’s vaccine, he was feeling confident about the shot but worried about making enough of it. Moderna had promised to make up to a billion doses during 2021. Imagine, he said, that Henry Ford was rolling the first Model T off the production line only to be told the world needed a billion of them.

Bancel calls the way covid-19 arrived just as messenger RNA technology was ready an “aberration of history.”

In other words, we got lucky.

Human bioreactors
The first attempt to use synthetic messenger RNA to make an animal produce a protein was in 1990. It worked but a big problem soon arose. The injections made mice sick. “Their fur gets ruffled. They lose weight, stop running around,” says Weissman. Give them a large dose, and they’d die within hours. “We quickly realized that messenger RNA was not usable,” he says.

The culprit was inflammation. Over a few billion years, bacteria, plants, and mammals have all evolved to spot the genetic material from viruses and react to it. Weissman and Karikó’s next step, which “took years,” he says, was to identify how cells were recognizing the foreign RNA.

As they found, cells are packed with sensing molecules that distinguish your RNA from that of a virus. If these molecules see viral genes, they launch a storm of immune molecules called cytokines that hold the virus at bay while your body learns to cope with it. “It takes a week to make an antibody response; what keeps you alive for those seven days is these sensors,” Weissman says. But too strong a flood of cytokines can kill you.

The eureka moment was when the two scientists determined they could avoid the immune reaction by using chemically modified building blocks to make the RNA. It worked. Soon after, in Cambridge, a group of entrepreneurs began setting up Moderna Therapeutics to build on Weissman’s insight.

Vaccines were not their focus. At the company’s founding in 2010, its leaders imagined they might be able to use RNA to replace the injected proteins that make up most of the biotech pharmacopoeia, essentially producing drugs inside the patient’s own cells from an RNA blueprint. “We were asking, could we turn a human into a bioreactor?” says Noubar Afeyan, the company’s cofounder and chairman and the head of Flagship Pioneering, a firm that starts biotech companies.

If so, the company could easily name 20, 30, or even 40 drugs that would be worth replacing. But Moderna was struggling with how to get the messenger RNA to the right cells in the body, and without too many side effects. Its scientists were also learning that administering repeat doses, which would be necessary to replace biotech blockbusters like a clotting factor that’s given monthly, was going to be a problem. “We would find it worked once, then the second time less, and then the third time even lower,” says Afeyan. “That was a problem and still is.”

Moderna pivoted. What kind of drug could you give once and still have a big impact? The answer eventually became obvious: a vaccine. With a vaccine, the initial supply of protein would be enough to train the immune system in ways that could last years, or a lifetime.

A second major question was how to package the delicate RNA molecules, which last for only a couple of minutes if exposed. Weissman says he tried 40 different carriers, including water droplets, sugar, and proteins from salmon sperm. It was like Edison looking for the right filament to make an electric lamp. “Almost anything people published, we tried,” he says. Most promising were nanoparticles made from a mixture of fats. But these were secret commercial inventions and are still the basis of patent disputes. Weissman didn’t get his hands on them until 2014, after half a decade of attempts.

When he finally did, he loved what he saw. “They were better than anything else we had tried,” he says. “It had what you wanted in a drug. High potency, no adverse events.” By 2017, Weissman’s lab had shown how to vaccinate mice and monkeys against the Zika virus using messenger RNA, an effort that soon won funding from BioNTech. Moderna was neck and neck. It quickly published results of an early human test of a new mRNA influenza vaccine and would initiate a large series of clinical studies involving diseases including Zika.

Pivoting to vaccines did have a drawback for Moderna. Andrew Lo, a professor at MIT’s Laboratory for Financial Engineering, says that most vaccines lose money. The reason is that many shots sell for a “fraction of their economic value.” Governments will pay $100,000 for a cancer drug that adds a month to a person’s life but only want to pay $5 for a vaccine that can protect against an infectious disease for good. Lo calculated that vaccine programs for emerging threats like Zika or Ebola, where outbreaks come and go, would deliver a -66% return on average. “The economic model for vaccines is broken,” he says.

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On the other hand, vaccines are more predictable. When Lo’s team analyzed thousands of clinical trials, they found that vaccine programs frequently succeed. Around 40% of vaccine candidates in efficacy tests, called phase 2 clinical trials, proved successful, a rate 10 times that of cancer drugs.

Adding to mRNA vaccines’ chance of success was a lucky break. Injected into the arm, the nanoparticles holding the critical instructions seemed to home in on dendritic cells, the exact cell type whose job is to train the immune system to recognize a virus. What’s more, something about the particles put the immune system on alert. It wasn’t planned, but they were working as what’s called a vaccine adjuvant. “We couldn’t believe the effect,” says Weissman.

Vaccines offered Moderna’s CEO, Bancel, a chance to advance a phalanx of new products. Since every vaccine would use the same nanoparticle carrier, they could be rapidly reprogrammed, as if they were software. (Moderna had even trademarked the name “mRNA OS,” for operating system.) “The way we make mRNA for one vaccine is exactly the same as for another,” he says. “Because mRNA is an information molecule, the difference between our covid vaccine, Zika vaccine, and flu vaccine is only the order of the nucleotides.”

95% effective
Back in March 2020, when the vaccine programs were getting under way, skeptics said messenger RNA was still an unproven technology. Even this magazine said a vaccine would take 18 months, at a minimum—a projection that proved off by a full nine months. “Sometimes things take a long time just because people think it does,” says Afeyan. “That weighs on you as a scientific team. People are saying, ‘Don’t go any faster!’”

The shots from Moderna and BioNTech proved effective by December and were authorized that month in the US. But the record speed was not due only to the novel technology. Another reason was the prevalence of infection. Because so many people were catching covid-19, the studies were able to amass evidence quickly.

Is messenger RNA really a better vaccine? The answer seems to be a resounding yes. There are some side effects, but both shots are about 95% effective (that is, they stop 95 out of 100 cases), a record so far unmatched by other covid-19 vaccines and far better than the performance of flu vaccines. Another injection, made by AstraZeneca using an engineered cold virus, is around 75% effective. A shot developed in China using deactivated covid-19 germs protected only half the people who got it, although it did stop severe disease.

“This could change how we make vaccines from here on out,” says Ron Renaud, the CEO of Translate Bio, a company working with the technology.

The potency of the shots, and the ease with which they can be reprogrammed, mean researchers are already preparing to go after HIV, herpes, infant respiratory virus, and malaria—all diseases for which there’s no successful vaccine. Also on the drawing board: “universal” flu vaccines and what Weissman calls a “pan-coronavirus” shot that could offer basic protection against thousands of pathogens in that category, which have led not only to covid-19 but, before that, to the infection SARS and probably other pandemics throughout history.

“You have to assume we’re going to have more,” Weissman says. “So instead of shutting down the world for a year while you make a new vaccine, we’ll have a vaccine ready to go.”

Last spring, Bancel began petitioning the government to pay for vast manufacturing centers to make messenger RNA. He imagined a megafactory that “companies could use in peacetime” but that could be quickly reoriented to churn out shots during the next pandemic. That would be insurance, he says, against a nightmare scenario of a germ that spreads as fast as covid but has the 50% fatality rate of Ebola. If “governments spend billions on nuclear weapons they hope to never use,” Bancel argued in April, then “we should equip ourselves so this never happens again.”

Later that month, as part of Operation Warp Speed, the US effort to produce the vaccines, Moderna was effectively picked as a national champion to build such centers. The government handed it nearly $500 million to develop its vaccine and expand manufacturing.

Beyond vaccines
After the covid vaccines, some researchers expect Moderna and BioNTech to return to their original plans for the technology, like treating more conventional ailments such as heart attacks, cancer, or rare inherited diseases. But there’s no guarantee of success in that arena.

“Although there are a lot of potential therapeutic applications for synthetic mRNA in principle, in practice the problem of delivering sufficient amounts of mRNA to the right place in the body is going to be a huge and possibly insurmountable challenge in most cases,” says Luigi Warren, a biotech entrepreneur whose research as a postdoc formed the nucleus of Moderna.

There is one application in addition to vaccines, however, where brief exposure to messenger RNA could have effects lasting years, or even a lifetime.

In late 2019, before covid-19, the US National Institutes of Health and the Bill and Melinda Gates Foundation announced they would spend $200 million developing affordable gene therapies for use in sub-Saharan Africa. The top targets: HIV and sickle-cell disease, which are widespread there.

Gates and the NIH didn’t say how they would make such cutting-edge treatments cheap and easy to use, but Weissman told me that the plan may depend on using messenger RNA to add instructions for gene-editing tools like CRISPR to a person’s body, making permanent changes to the genome. Think of mass vaccination campaigns, says Weissman, except with gene editing to correct inherited disease.

Right now, gene therapy is complex and expensive. Since 2017, several types have been approved in the US and Europe. One, a treatment for blindness, in which viruses carry a new gene to the retina, costs $425,000 per eye.

A startup called Intellia Therapeutics is testing a treatment that packages CRISPR into RNA and then into a nanoparticle, with which it hopes to cure a painful inherited liver disease. The aim is to make the gene scissors appear in a person’s cells, cut out the problem gene, and then fade away. The company tested the drug on a patient for the first time in 2020.

It’s not a coincidence that Intellia is treating a liver disease. When dripped into the bloodstream through an IV, lipid nanoparticles tend to all end up in the liver—the body’s house-cleaning organ. “If you want to treat a liver disease, great—anything else, you have a problem,” says Weissman.


But Weissman says he’s figured out how to target the nanoparticles so that they wind up inside bone marrow, which constantly manufactures all red blood cells and immune cells. That would be a hugely valuable trick—so valuable that Weissman wouldn’t tell me how he does it. It’s a secret, he says, “until we get the patents filed.”

He intends to use this technique to try to cure sickle-cell disease by sending new instructions into the cells of the body’s blood factory. He’s also working with researchers who are ready to test on monkeys whether immune cells called T cells can be engineered to go on a seek-and-destroy mission after HIV and cure that infection, once and for all.

What all this means is that the fatty particles of messenger RNA may become a way to edit genomes at massive scales, and on the cheap. A drip drug that allows engineering of the blood system could become a public health boon as significant as vaccines. The burden of sickle-cell, an inherited disease that shortens lives by decades (or, in poor regions, kills during childhood), falls most heavily on Black people in equatorial Africa, Brazil, and the US. HIV has also become a lingering scourge: about two-thirds of people living with the virus, or dying from it, are in Africa.

Moderna and BioNTech have been selling their covid-19 vaccine shots for $20 to $40 a dose. What if that were the cost of genetic modification, too? “We could correct sickle-cell with a single shot,” Weissman says. “We think that is groundbreaking new therapy.”

There are fantastic fortunes to be made in mRNA technology. At least five people connected to Moderna and BioNTech are now billionaires, including Bancel. Weissman is not one of them, though he stands to get patent royalties. He says he prefers academia, where people are less likely to tell him what to research—or, just as important, what not to. He’s always looking for the next great scientific challenge: “It’s not that the vaccine is old news, but it was obvious they were going to work.” Messenger RNA, he says, “has an incredible future.”
https://www.technologyreview.com/2021/0 ... covid-hiv/
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Re: DNA and RNA

Post by NineBerry » Sat Feb 06, 2021 4:11 pm

Yay for science and technology

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Re: DNA and RNA

Post by Tero » Sat Feb 06, 2021 10:09 pm

Wait till they try to cure stuff with these in America. Think of all the side effects lawyers can sue for!
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Re: DNA and RNA

Post by JimC » Mon Feb 08, 2021 8:09 am

NineBerry wrote:
Sat Feb 06, 2021 4:11 pm
Yay for science and technology
Yeah but ancient writings from bronze age goat herders are where the real truth exists!
Nurse, where the fuck's my cardigan?
And my gin!

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Re: DNA and RNA

Post by Tero » Wed Mar 31, 2021 9:46 pm

Somewhat related to the vaccine wrk, RNA etc.
The world's most exensive drug
https://en.wikipedia.org/wiki/Onasemnogene_abeparvovec

https://www.cnn.com/2021/03/31/health/t ... index.html
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If you don't eat your meat, you can't have any pudding!
How can you have any pudding if you don't eat your meat?
You! Yes! You behind the bike sheds! Stand still, laddie!

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