Unless you are old or chronically sick, it’s likely that the only drug you’ve ever taken that hasn’t been a small molecule is a vaccine. Indeed, drugs that aren’t small molecules are so strange and rare we usually don’t think of them as “drugs” but as a separate entity: vaccines, monoclonal antibodies, anabolic steroids.
But, like, the vast majority of molecules found in our body, and in all of organic life, are not classified as “small”. And the vast majority of the things doing something interesting are not really molecules, but more so fuzzy complexes of molecules (ribosomes, lysosomes, lipoproteins, membranes).
So why are virtually all drugs small molecules? Prima facie we’d expect most of them to be complexes made up of 10s to 1000s of very large molecules.
The answer lies in several things:
- Easy to mass-produce
- Simple to administer
- Cheap to store
- Homogenous in effect
- Quick to act
Medicine is slowly undergoing the process of learning how to work with complex molecules. In parallel with normal medicine, I’d like to think that biohackers with the ability to custom order whatever they can dream of, will lead the way with self-experimentation. Figuring out the limits and benefits from individualized design and continuous monitoring. For now, this is mainly click-bait, people injecting a bioluminescence gene with CRISPR kinda stuff, but some of it isn’t. As an example, the guy from ThoughtEmporium self-designed a therapy to get rid of lactose intolerance (though the solution is not permanent, it lasts for a few months). 100s of other such people are engaging in similar experiments, and the more people do it, the more resources become available, the easier it will get, and the better the ROI. As this happens, social acceptance will follow and pharmaceutical companies will get more on the deal.
Tag: medicine
Universal Tick Vaccine
Over 10 diseases can be transmitted by tick bites. The most well-known is Lyme disease, caused by a bacterium called Borrelia burgdorferi. In the past, vaccines have successfully been developed to specifically target this Lyme disease bacterium. However, this new vaccine candidate takes a different approach, using mRNA technology to target the tick itself. This particular vaccine directs cells to produce a number of proteins found in the saliva of the black-legged tick Ixodes scapularis. This vaccine is unique in the way it targets a carrier of a pathogen rather than the pathogen itself. This means it should offer a broad-based protection from all kinds of tick-induced disease and not just a single pathogen. “When you feel a mosquito bite, you swat it. With the vaccine, there is redness and likely an itch so you can recognize that you have been bitten and can pull the tick off quickly, before it has the ability to transmit B. burgdorferi.”
2022-02-24: A gene drive might be an alternative:
This approach is already being applied to malaria-transmitting mosquitoes, but scientists have run into a wall trying to use CRISPR to prevent tick-borne diseases — or, more accurately, a hard shell. The problem is that scientists need to be able to insert their CRISPR system into ticks when they’re at the embryo stage. But ticks grow in eggs coated in a hard wax, which can literally shatter the glass needles used for injections. “Previously, no lab has demonstrated genome modification is possible in ticks. Some considered this too technically difficult to accomplish.” They have now demonstrated 2 different techniques that make gene editing a viable option for fighting tick-borne diseases. So far, all we know is that it’s possible to get a CRISPR system into ticks — we still don’t know what edits, if any, can prevent the spread of tick-borne diseases.
Astrocytes
The star-shaped cells usually help clear away toxic particles that build up in the brain naturally or after head trauma, and are supposed to nourish neurons. But laboratory tests on mice show astrocytes also release toxic fatty acids to kill off damaged neurons, confirming a suspicion many neurologists have had for years. “Our findings show the toxic fatty acids produced by astrocytes play a critical role in brain cell death. The results provide a promising new target for treating, and perhaps even preventing, many neurodegenerative diseases”.
Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system.
SARS-CoV-2 Life Cycle
What has emerged from 19 months of work, backed by decades of coronavirus research, is a blow-by-blow account of how SARS-CoV-2 invades human cells. Scientists have discovered key adaptations that help the virus to grab on to human cells with surprising strength and then hide itself once inside. Later, as it leaves cells, SARS-CoV-2 executes a crucial processing step to prepare its particles for infecting even more human cells. These are some of the tools that have enabled the virus to spread so quickly and claim millions of lives.
Lockdown Effectiveness
1: Various policies lumped together as “lockdowns” probably significantly decreased R. Full-blown stay-at home orders were less important than targeted policies like school closures and banning large gatherings. Talking about which ones were “good” or “bad” is an oversimplification compared to the more useful questions of when countries should have started vs. stopped each to be on some kind of Pareto frontier of lives saved vs. cost.
2: If Sweden had a stronger lockdown more like those of other European countries, it probably could have reduced its death rate by 50-80%, saving 2500+ lives.
3: On a very naive comparison, US states with stricter lockdowns had ~20% lower death rates than states with weaker ones, and ~0.6% more GDP decline. There are high error bars on both those estimates.
4: Judging lockdowns by traditional measures of economic significance, moving from a US red-state level of lockdown to a US blue-state level of lockdown is in the range normally associated with interventions that are debatably cost-effective/utility-positive, with error bars including “obviously good” and “pretty bad”. It’s harder to estimate for Sweden, but plausibly for them to move to a more European-typical level of lockdown in the early phase of the pandemic would have very much cleared the bar and been unambiguously cost effective/utility-positive.
5: It’s harder to justify strict lockdowns in terms of the non-economic suffering produced. Even assumptions skewed to be maximally pro-strict-lockdown, eg where strict lockdowns would have prevented every single coronavirus case, suggest that it would have taken dozens of months of somewhat stricter lockdown to save one month of healthy life. This might still be justifiable if present strict lockdowns now prevented future strict lockdowns (mandated or voluntary), which might be true in Europe but doesn’t seem as true in the US.
6: Plausibly, really well-targeted lockdowns could have been better along every dimension than either strong-lockdown areas’ strong lockdowns or weak-lockdown areas’ weak lockdowns, and we should support the people trying to figure out how to do that.
7: All of this is very speculative and affected by a lot of factors, and the error bars are very wide.
Put Silk in it
Researchers kept searching for the path to engineered silk. Yet, year after year, they failed. Each ran into scaling issues, production costs, and regulatory due diligence. After all this time, silk-based tech is weaving its way into health care, the food industry, and clothing.
SilkVoice is a gluey mix of hyaluronic acid and microscopic particles of regenerated silkworm silk meant to treat vocal fold disorders. SilkVoice is authorized for human use. The majority of the 40 people who have received the injections have retained their improvements.
Mori has commercialized silk as a way of protecting food. Unlike wax, Mori’s coating can cling to both water-repellent and porous surfaces, like the outside and inside of a zucchini. Mori already has pilots running at farms and food companies around the US, and larger-scale manufacturing is supposed to start later this year.
Kraig Labs claims to have produced the first “nearly pure” spider silk fabricated by silkworms and has scaled up production. It has partnered with a company in Singapore to make luxury street wear and is working with Polartec on performance outerwear. The company is also considering biomedical uses and bullet-resistant protective apparel.
Purdue University engineers have developed a method to transform existing cloth items into battery-free wearables resistant to laundry. These smart clothes are powered wirelessly through a flexible, silk-based coil sewn on the textile. “By spray-coating smart clothes with highly hydrophobic molecules, we are able to render them repellent to water, oil and mud. These clothes are almost impossible to stain and can be used underwater and washed in conventional washing machines without damaging the electronic components sewn on their surface.”
Dengue Progress
Her team released Wolbachia-carrying mosquitoes in parts of Yogyakarta as part of a randomized controlled trial. Wolbachia rapidly spread among the local mosquitoes, and reduced the incidence of dengue by 77%. “That provides the gold standard of evidence that Wolbachia is a highly effective intervention against dengue. It has the potential to revolutionize mosquito control.”
Expert COVID-19 long-haulers
Most of the other treatments haven’t had the funds for extensive trials, and without proper research, some drugs run the risk of getting overhyped based on limited information. “The early bets financially were made on investing in vaccine trials and investing in monoclonal antibodies. What received relatively less funding and attention were drugs that were already FDA-approved that could be repurposed for COVID.” his goal with COVIDSalon is to provide a dedicated hub of treatment information so people don’t have to sift through a barrage of old articles. A large segment of COVIDSalon aims to help COVID long-haulers. At the moment, only a small number of trials are focusing on long-haulers. James also highlights drugs like fluvoxamine that have alleviated long-term symptoms in a test of COVID-19 patients, plus others such as the nutritional supplement GlyNAC, which is worth watching but is still in very early-stage trials. The way that long-haulers have organized throughout the pandemic—discussing their symptoms in Facebook and Slack groups, and pushing medical professionals to pay attention to their ailments—echoes the patient advocacy that James helped popularize during the AIDS epidemic. Through publications such as ATN, many people with AIDS knew as much about the latest niche medical findings as licensed doctors did. “I think that’s the same with the long-haulers. Everyone is learning about the long-term consequences of this in real time.”
Human Challenge Trials
we need far more human challenge trials, and far less garbage people like ethicists.
In interviews, former challenge trial participants described motives for their participation that ranged from the light-hearted — several imagined it would be a fun story to tell at scientific conferences and parties — to the serious. Some spoke of altruistic motives, often shaped by personal experiences. “I spent a couple years in Africa; I was in the Peace Corps. I think for me, seeing that firsthand, and knowing that there might be some way that maybe I can be a part of figuring out whether or not we can make a vaccine for malaria definitely played a big part in it for me.”
Kati Kariko
Kati is a leading candidate for a Nobel. Amazing work.
1 fateful day, the 2 scientists hovered over a dot-matrix printer in a narrow room at the end of a long hall. A gamma counter, needed to track the radioactive molecule, was attached to a printer. It began to spew data.
Their detector had found new proteins produced by cells that were never supposed to make them — suggesting that mRNA could be used to direct any cell to make any protein, at will.
“I felt like a god,” Dr. Kariko recalled. [..] On Nov. 8, the first results of the Pfizer-BioNTech study came in, showing that the mRNA vaccine offered powerful immunity to the new virus. Dr. Kariko turned to her husband. “Oh, it works. I thought so.” To celebrate, she ate an entire box of Goobers chocolate-covered peanuts. By herself. Dr. Weissman celebrated with his family, ordering takeout dinner from an Italian restaurant, “with wine”. Deep down, he was awed.
“My dream was always that we develop something in the lab that helps people”. I’ve satisfied my life’s dream.” Dr. Kariko and Dr. Weissman were vaccinated on Dec. 18 at the University of Pennsylvania. Their inoculations turned into a press event, and as the cameras flashed, she began to feel uncharacteristically overwhelmed.
A senior administrator told the doctors and nurses rolling up their sleeves for shots that the scientists whose research made the vaccine possible were present, and they all clapped. Dr. Kariko wept.
Gregor J. Rothfuss 