Plasmid errors and regulatory fails on drug shortage

And another smoker's win in this pandemic

I thought of starting this article with text, but I'd rather start it with… a meme.

My goal today was to publish my Long Covid article but after properly reading the study, it ended up being much, much more complex than I previously thought. I guess the short vacation, away from electronics 99% of the time did wonders for my cognition. First, the Plasmid opsie, or what I wrote on Twitter as “sucks to suck” news of the day.

Serious errors plague DNA tool that’s a workhorse of biology

Researchers analysed thousands of laboratory-made plasmids and discovered that nearly half of them had defects, raising questions of experimental reproducibility.

Laboratory-made plasmids, a workhorse of modern biology, have problems. Researchers performed a systematic assessment of the circular DNA structures by analysing more than 2,500 plasmids produced in labs and sent to a company that provides services such as packaging the structures inside viruses so they can be used as gene therapies. The team found that nearly half of the plasmids had design flaws, including errors in sequences crucial to expressing a therapeutic gene. The researchers posted their findings to the preprint server bioRxiv last month ahead of peer review¹.

The study shines a light on “a lack of knowledge” about how to do proper quality control on plasmids in the lab, says Hiroyuki Nakai, a geneticist at Oregon Health & Science University in Portland who was not involved in the work. He was already aware of problems with lab-made plasmids, but was surprised by the frequency of errors uncovered by the study. There are probably many scientific papers that have been published for which the results are not reproducible owing to errors in plasmid design, he adds.

The most rampant errors Lahn and his colleagues found were related to a key gene-therapy tool. Therapies are often packaged into adeno-associated viruses (AAVs), which are mostly harmless and can ferry treatments to cells. When making the plasmids for these AAVs, researchers sandwich a therapeutic gene between sequences called ITRs, which play a crucial part in ensuring that the gene gets packaged into the virus for delivery. In essence, these sequences send a biological signal to cells that says “I belong in this virus”. But the team found that about 40% of the AAV plasmids in the study had mutations in the ITR regions that could garble this important message. If researchers were to use these misdesigned plasmids, their gene therapy might not work — and it could take the scientists a long time to find out why.

Plasmids used in many laboratory settings for basically any advanced biology work today have severe flaws that affect the outcome of anything using plasmids. Production of proteins, research, gene delivery. The irony will most assuredly not be lost on you, when you finish this article, because failing to even properly assess cutting edge technology on one side, and…

Another “problem” is a recent rabbit hole, my friend First Contact Newsletter sent me on. During our conversations sometimes my brain suddenly connects dots at an exponential rate, missing pieces. It is very complicated because I need to trace back each “accident”, and “coincidences” since 2020 to whatever that disruption affected. Industrial chemistry is quite tiresome.

As the world's geopolitical structure shifts, we must return once more to a topic I have kept track of for over 2 years. Drug shortages and we have some new information pinning the blame on the actual culprits, sclerotic governmental agencies. As one could come to expect, given the myriad of different circumstances, the cancer drug shortage persists. Another source.

The government offers little solution, just propositions, and more propositions, the shortage is drastic enough to affect even clinical trials.

But among the surveyed centers that reported drug shortages, 43% indicated that the shortages have impacted clinical trials at their center, leading to greater administrative burdens, reductions in trial enrollments, reductions in open trials, and budget changes, among other disruptions.

It’s not just the large cancer centers that are part of the National Comprehensive Cancer Network that are experiencing these drug shortages.

While structurally I would prefer the next piece at the end, it is contextually better here. To make matters worse, the US, EU, and NATO are heavily antagonizing China, and pushing India into Russia’s arms, which is a significant problem among many necessary cogs for systemic function, but here it is drug production. Both China and India dominated the drug and API (ingredients necessary for drug manufacturing) production.

Chinese Company Under Congressional Scrutiny Makes Key U.S. Drugs

Lawmakers raising national security concerns and seeking to disconnect a major Chinese firm from U.S. pharmaceutical interests have rattled the biotech industry. The firm is deeply involved in development and manufacturing of crucial therapies for cancer, cystic fibrosis, H.I.V. and other illnesses

From a national security perspective, I would fully and completely understand the necessity to remove adversarial strongholds on critical sectors of your economy, or society. Under normal circumstances, not under a persistent, long-lasting drug shortage affecting a myriad of diseases, both chronic, acute, seasonal, or long-lasting.

I recommend you read the NY Times article in its entirety, to understand the sizable scope of the involvement of Chinese biotech in the US, but especially WuXi in the production of basically all new, leading treatments of leading Western pharmaceutical companies. Similar to how Raytheon’s CEO once said “We don’t plan or are even capable of fully decoupling from China”, the same can be said for drug manufacturing, at least short-term.

To either your surprise or the surprise of no one, among the many reasons for the persistent, now years-long drug shortage, lies regulatory hurdles imposed by sclerotic federal agencies. A recent study by the European Commission points exactly to that, “MAHs regard manufacturing and logistical issues as the main reasons for supply chain discontinuities, and in few instances, regulatory issues”.

Cyprus, the UK, and many smaller and poorer European countries are experiencing shortages. Europe is becoming the end of many jokes of multiple industries precisely because of its engrained desire to regulate everything. To my complete surprise, one of the most covered shortages since the start of this pandemic isn’t entirely driven by over-prescription, demand growth, or production disruption. The Adderal shortage.

For the DEA, Operation Bottleneck was a step toward redemption. During the painkiller epidemic, as state attorneys general and local governments brought hundreds of cases against opioid manufacturers and distributors, they routinely cited the DEA’s poor monitoring of the companies’ records as a factor that helped flood the country with OxyContin and similar drugs. Those suits eventually compelled large drug companies to pay $26 billion — the biggest such settlement since the tobacco case of 1998. “DEA got the crap beat out of them,” says Krista Tongring, a former section chief in the agency’s office of compliance who now consults for Ascent. “They’re like, ‘We have to do something.’”

Ascent’s lawsuit against the DEA describes the agency’s sanctions as “a clear and ill-conceived overcorrection and reaction to the criticism it received for mishandling of opioid abuse.” The suit also goes further, alleging that the DEA’s action reflects “a drug policy that is focused on controlling supply.” That language comes close to accusing the DEA of backdoor policy-making through regulation, as if the shortage of ADHD medications is the agency’s intent. Experts I spoke to dismissed that theory as far-fetched. “The DEA is a pretty straight agency. I can’t see them getting together with the FDA and saying, ‘Let’s just restrict quota.’ There must be a justification to increase or decrease quota,” says Joseph Rannazzisi, a former deputy assistant administrator of the DEA office of diversion control, the division that investigates the pharmaceutical industry.

That said, Rannazzisi — who was one of the first DEA officials to challenge drug companies for feeding the country’s nascent opioid addiction in the mid-2000s — is alarmed by the rapid rise in prescriptions for Adderall and similar drugs in recent years. “Everybody is concerned about the increase in use of stimulants, not just the DEA and the FDA,” says Rannazzisi. “The bottom line is that I think we do have a problem.”

For Ascent, one of the more frustrating parts of being told by the government to stop making Adderall is that other parts of the government have pleaded with the company to make more. The company says that on multiple occasions, officials from the FDA asked it to increase production in response to the shortage, and that Ron Wyden, the Democratic senator from Oregon, also pressed Ascent for help. They received responses similar to those the company gave the stressed-out callers looking for pills: Ascent didn’t have any information. Instead, the company directed them to the DEA.

I missed this article a few months ago, so besides demand growth during the pandemic, the initial shortage and the myriad of cascade events that led to a years-long shortage of Adderall was regulatory arrogance from the DEA, together with a disruption with the FDA, which is a common dynamic between federal agencies, one wanting power over the other (quite literally what is happening with avian flu right now, FDA x CDC).

Another agency that is at the center of the drug shortage and will make that, and many other chemicals increasingly scarce is the EPA. “Historic Drug Shortage Exacerbated by EPA Overreach”, a few chemicals that are critical not just to drug manufacturing but to modern life itself. Lo and behold, the EPA wants to heavily regulate and disrupt the domestic production of some of these.

It is somewhat ironic that the government and politicians state one thing, and its many entrenched bureaucratic machines do the exact opposite as if they abide by other rules. So, once again, the same recommendations I had for a couple of years stand.

If you need or use certain drugs, build a stash, at the very minimum you will save money, if the worst case scenario happens, a large conflict between the Asian axis and the West, you have a buffer. The worst outcome, you “just” saved money from inflationary trends. Given the current research that I am doing on chemicals, “accidents”, “coincidences” and the information presented here, especially in regard to regulatory agencies.

I don’t expect the drug shortage to improve this year or the next. It may as well be a “2020’s” thing. I will keep the subjects separated, but this will play a part in the Fourth Option’s “larger conspiracy” on chemicals. And to add a final flair of interesting coincidences.

Both China and India have experienced drug shortages, in particular, the most interesting case is China, given it is the world’s leading producer of basically everything. How in God’s green Earth do the leading manufacturers also experience shortages ? This is beyond me.

To finish this article in higher spirits, and to drive a point I a couple of times to home.

Source

So researchers analyzed the current strain of Highly Pathogenic Avian Influenza, H5N1, that infected a few poultry workers so far, and untold amounts of cattle, and found out that we may have CD8+ T Cell protection, the type of protection I have argued since the start it is the one you want, and the one needed to avoid severe infection.

You may get sick but with the sniffles rather than influenza that steadfastly becomes pneumonia. So at this point, one of my observations is backed by evidence and is true. The only way we get Avian Influenza, especially a H5N1 pandemic in humans is by someone engineering a new strain, or a laboratory working on gain of function (remember, the White House made SARS-CoV-2, Influenza, and Ebola Gain of function permissible) suffering a leak.

This leaves something else, that has to be engineered as the potential next pandemic… but this is a talk for a conspiracy day. And merely for self-amusement.

Former and current smoking, as well as an increased predicted anti-S IgG titer were significantly associated with a lower risk of Omicron infection.

Common Smokers W during the entire pandemic hahahaha. A reminder that cigarette smoke attenuates the infection with the H7N9 avian influenza virus. Don’t start smoking, but if you are a smoker, don’t stop it. My mom remains unphased by all assortment of diseases…

I will now focus on the Long Covid-Galectin 9 article, and the chemical conspiracy one, I will try to publish it by Sunday, but I will publish when I publish it, quality, over quantity. I wish you all a great weekend.


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