Science: Pick your own rabbit hole

Geneticist Nicola Dennis thinks doing your own research makes sense and offers some tips on going about it the scientific way.

It says a lot that I feel a crushing sense of responsibility to reveal my Covid-19 vaccination status before I can deliver you an innocuous article on vaccine research.

I know I should resist and keep you guessing because it is so far beyond the point that it is a mere speck on the horizon. But I don’t want to spend eternity trying to shake off the social media immune system once it has labelled me this or that. So, pigeonhole me in “double vaccinated, but wary of vaccine mandates”, please.

Despite the overwhelming majority of Kiwis rolling up their sleeves to get their jab, we seem to feel the need to ramp the political pressure up to fever-pitch and scream at each other.

I don’t care if you plan to get the vaccine or not. I know you have your reasons for your choices. I take the vaccine for my own personal safety and try to avoid the moral panic about what other people do with their own deltoids. Less hand wringing and more hand washing, I say. Oh, and how about properly funding the health sector, eh? Couldn’t hurt.

Doing your own research, why not?

I am very much in favour of doing your own reading. The near entirety of human knowledge now sits within arm’s reach at all times. It makes sense to take a peek. But, when someone starts talking about new world orders and lizard people, I have to assume we aren’t looking in the same corners of the internet.

Let me tell you how I find my information. The University of Otago has given me a few fancy certificates that say I have some proficiency in this area. Who knows, maybe I can be of some help.

Google Scholar and Wikipedia

Hands and feet inside the bus of impartiality at all times, while we take a quick tour through some vaccine literature on Google Scholar (scholar.google.com).

Before we begin, I want to point out that, for most people and most topics, Google Scholar is overkill. Wikipedia (www.wikipedia.org) is a decent source of information for most things.

You shouldn’t trust Wikipedia for hard-to-source or very fresh information. Don’t use it to find out how many kids Boris Johnston has, but it’s usually pretty solid for medical or scientific topics.

Overt medical misinformation/politicking is unlikely to get past the eagled-eyed crowds of interested parties (researchers, medical practitioners, activists, political science majors etc) that watch the Wikipedia pages.

While anyone can log in and change a Wikipedia article, the process is deterring enough that only the most invested will bother. Wikipedia is basically a crowd-sourced method of peer review and I think it does it fine.

Finding peer reviewed articles

Google Scholar is a sacred place in which to search science journals, patents, court cases and textbooks. You could type anything in here and be offered a smorgasbord of peer-reviewed content.

Whenever I am looking into a topic I am unfamiliar with, I like to start with a review article. As opposed to general science articles which are reporting on new scientific findings (recognised by the methods, results, discussion layout that we were all subjected to at school), a review is designed to summarise the findings to date.

In contrast to general science papers which can be the reading equivalent of eating glass, reviews usually have to be well written and understandable to make it past the editorial gatekeepers at the scientific journals.

I am interested in mRNA vaccines so I type mRNA vaccines review into Google Scholar.

The first article1 is “Brief review of the mRNA vaccines Covid‑19” available on springer.com. I like it’s promise of brevity, but I am a bit put off by the grammar in the title. I can see from the green text just under the link that it was published in 2021 which is usually what I want.

There’s no point having an outdated review. But, for now, I would like something a bit more general and something that pre-dates the pandemic. I want to know what the scientists were discussing before they had ever heard of Covid-19. So the second search result2 “mRNA vaccines – a new era in vaccinology” published in Nature in 2018 looks more like my cup of tea.

Nature is a well-known journal and I can see that this review has been cited (mentioned in other articles) over 1000 times. This looks like a good bit of literature to cut my teeth on.

Even better, it is available for free. In an ideal world they would always be free. It is an annoying quirk of the scientific process that publicly funded science often lives behind paywalls even though the journals extract their publishing costs out of the authors submitting the work. It’s a very bizarre business model that, quite frankly, could only have been dreamed up at a university.

If an article can’t be found for free, it is dead to me. Let the toffs clinging to their outdated paywalls wail into obscurity. Plenty more fish in the sea.

Reading the first review – focus on the messenger (RNA)

If you are following along at home, you have probably noticed that my chosen review is 19 pages long. Hey, I never said this was easy. If you want it easy, then chat with the bot on the Ministry of Health website. There is a reason why university professors often look like Gandalf the White.

Besides, we will not be delving deep into all 19 pages. Four of those pages are references to papers the authors have cited. The authors have thoughtfully put comments on their best references – you usually don’t get that kind of service. But, we don’t need these references unless we find a rabbithole in the main text that we would like to follow.

Also, quite a bit of the review is dedicated to mRNA cancer treatments. The review lists nearly 60 clinical trials with mRNA vaccines against cancer taking place in some 19 organisations around the world. It seems that there are some advanced melanoma patients that have been given a new lease on life after some of their immune cells were treated with anti-tumor mRNA vaccines. This is thanks to trials that have been taking place in mice since-1996. It’s all fascinating stuff, but it’s not what we came for.

Instead let’s jump into the introduction of this review. As per tradition, the authors start by framing the problem.

Vaccines are useful to prevent or treat disease, but vaccines that rely on weakening or killing the pathogen are not suitable for the proper nasty stuff like HIV and Ebola. And, vaccines that rely on synthesising certain proteins of the pathogen are difficult to make.

As we have discussed in previous articles about fake meat etc, protein chemistry is difficult. Humans can make proteins in the lab but the speed at which we can devise a production system for each new protein is comparable to a toddler learning to assemble a Ferrari. There needs to be, says the review, a quicker way to come up with new vaccines in response to new pathogens.

Our bodies are experts at making proteins, what if we just temporarily tricked our bodies into making the vaccine protein? If we could work out a reliable method of doing that then all we would have to worry about, for each new pathogen, is the genetic information for the protein we want.

We would not have to burn years trying to work out which methods of protein expression, purification and chemical environments suit this protein in the lab. And, by the way, we can use the same methods to train our immune system to attack cancer cells.

I can only imagine the dismay of the authors when it transpired that rapid vaccine development also breeds a fair bit of public distrust.

The review says that scientists have been testing DNA and RNA vaccines in mice using reporter genes since 1990. Reporter genes are simply genes that have very obvious effects. Yes, I have found a way to talk about glow-in-the-dark animals again. If we look up that reference3 next to the reporter gene statement (it is listed as reference 5) using Google Scholar or the link provided, then we can see that the firefly luciferase was one of the genes used. Glow, mice, glow.

According to our review article, the science hype cycle backed the wrong horse for a while and focused on DNA, rather than the RNA side of things. This was because RNA was considered to be too unstable. Now, after a lot of poking and prodding, we understand more about RNA and we are in a better position to tame it for our use.

Smuggling RNA into the body

Sending an RNA shopping list to someone’s cells was obviously very appealing back in 2018, even without the pandemic. There was just the small problem of how to sneak the mRNA past the very immune system they were trying to tickle.

Your body does not want to be tricked into making foreign proteins. Rather poetically, tricking your body into producing proteins is exactly what viruses do. So, one of your body’s first lines of defence is to detect RNA that doesn’t belong and destroy it.

Getting past the immune system to make the protein was the chief technical challenge holding back mRNA vaccines when this review was written. The review goes over 12 different methods of mRNA vaccine delivery that might be promising.

It also details methods of cleaning the mRNA (if your mRNA is loitering with random misfigured bits of RNA and DNA that is going to look suspicious) and modifying the mRNA so that it looks less foreign and the protein actually gets sent to the correct place. For vaccine purposes, we want the protein exported to the bloodstream where it can run an futile OJ Simpson-style police chase around your circulation and get every authority on high alert.

The second review and beyond

Through the power of hindsight, and the brief review1 of mRNA vaccines for Covid-19 paper mentioned earlier, we can see that encapsulating the mRNA in lipid nanoparticles was the golden ticket to getting past the immune checkpoint and into the protein factory.

This other review is brief, as promised. But it gives us some good articles that we might like to look up. It gives some references for the rate of severe allergic reactions following the vaccines (2.5 to 11.1 anaphylaxis events per million doses, mostly in people with a known history of anaphylaxis) and points to some preliminary findings on the duration of the protective immunity. Pick your rabbit hole and choose your own adventure from here on in.

DNA AND RNA EXPLAINED

Let’s power through some biology basics. DNA contains the genetic information for the proteins needed to build us, but for very good reasons, it is trapped in a protective castle inside the cell called the nucleus. DNA sends coded messages out through the nucleus, into the main body of the cell to tell its workers what to do. These messages are made of RNA. There are a few different types of RNA, but the one we are interested in is messenger RNA (mRNA). This is literally the message for a protein. I would like one protein please, it needs to be this long, with these amino acids in this particular order and when you are done can you tie it up into a bird nest of knots and send it to this address, thanks.

References
1. Vitiello A, Ferrara F. Brief review of the mRNA vaccines COVID-19. Inflammopharmacology. 2021;29(3):645-649. doi:10.1007/s10787-021-00811-0
2. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261-279. doi:10.1038/nrd.2017.243
3. Wolff JA, Malone RW, Williams P, et al. Direct Gene Transfer into Mouse Muscle in Vivo. Science. 1990;247(4949):1465-1468. doi:10.1126/science.1690918