Good morning, John.

So if you asked me a couple of years ago what I thought the most deadly infectious disease in the world was, I probably would have started out with malaria. And then if you told me I was wrong after that, I probably would have gone to AIDS. And then, yeah, I would have needed a hint, you know. I would have needed a hint to get to tuberculosis, which is weird because it has been the most deadly infectious disease for like 99% of the last 10,000 years. Like every once in a while, like, Spanish flu or the Black Death or, for a very brief time there, COVID will overtake tuberculosis, but then tuberculosis will take its title back as it has now. It's actually a strong contender for the oldest infectious disease—so it's been with us for a long time—and I would love to like read a John Green book about it. Like you are definitely the expert on this one. Not long ago I thought tuberculosis was like pneumonia, where it was, like, describing more symptoms, like a thing that happened to the body rather than a specific disease—but no. Tuberculosis is caused by a specific bacteria. And there are a bunch of reasons why this bacteria is extra good at being bad, but one of the big ones is this.

This is the cell wall of the tuberculosis bacteria. And if you think that that looks like a weird lookin' cell wall, you're right. It's weird lookin'. It's weirdly thick. It is in many different ways the tuberculosis bacteria's secret weapon. This big thick cell wall that's composed of largely, like, waxy fats makes it so much harder to fight tuberculosis in so many different, weirdly different ways. So first of all, you could guess maybe get some of the obvious ways. Like it's a big fat cell wall so it's hard to get stuff through it into the cell like antibiotics that might kill that cell. But also, a lot of antibiotics work specifically by attacking the cell wall of bacteria. It's very different from the cell membranes of people, so you can go after that specific weird thing about bacteria and break it and then the bacteria dies. But, that works on normal cell walls. So because the cell wall is so different, a lot of antibiotics just don't work as well on TB.

And then there's some slightly less obvious ways that this cell wall helps out tuberculosis. Like for example, we think that it makes it, like, easier for it to create biofilms, like really strong biofilms where lots of bacteria work together to create, like, structures that are broader than individual bacteria. Biofilms make it harder for antibiotics to get in and harder for immune cells to get in, allowing the tuberculosis to figure out how to, like, hold on for a really long time inside the body. And also, having a bigger weirder cell wall gives the tuberculosis bacteria more opportunities to evolve resistance to antibiotics. There's just more places for resistance to evolve. It's called cell wall remodeling and TB is really good at it. But then, there's, like, in my head, the really surprising ways that this helps out tuberculosis. Because this cell wall is so big and complicated, it's actually very difficult to manufacture, which means that tuberculosis grows really slowly. Like, it replicates much more slowly than most bacteria, which sounds like it would make it worse at being a pathogen, but no.

So first of all, a lot of antibiotics target fast replicating cells and tuberculosis just isn't a fast replicating cell, so those antibiotics are less good at attacking tuberculosis. But second and this is the really weird one and it's just a flaming coincidence, we, in order to treat tuberculosis, have to figure out whether a person has tuberculosis and if so, what kind they have and what antibiotics it might be resistant to. And to do that, you have to take, like, the spit of a person and see what bacteria grows in a petri dish. And this is easy for most bacteria because the bacteria grows super fast. Like a well-fed E. coli colony will double in size every 20 minutes. For tuberculosis that takes about a day. In order to diagnose tuberculosis, you have to grow it in the petri dish. And to see if it's resistant to antibiotics, you have to do that a bunch of different times, exposing it to a bunch of different antibiotics which is just a lot of human labor. Like it takes a lot of time, a lot of petri dishes, and a lot of space, which would be fine if, like, a thousand people a year got tuberculosis, but, like, 10 million people a year get tuberculosis.

But, we have now sequenced a bunch of different TB strains and we know the sequences that are responsible for antibiotic resistance. And that allows us, with this machine, to run a sample through a little card cartridge that will tell you if those genetic sequences are there. That tells you two things: One, that it's tuberculosis and two, whether or not it's resistant to antibiotics. That machine can do tons of different tests for tons of different diseases and it does those tests all over the world. But since TB is the world's most deadly infectious disease, and since it largely hits in communities that do not have a lot of resources, and because it kills millions of people per year and disables many more and has been doing that for many many many years, it is so so so important that we get the cost of these tests as low as possible. Specifically for multi-drug resistant TB, which is just a very dangerous disease for everybody in the world. In large part because of its weird cell wall, tuberculosis is just really good at evolving resistance to antibiotics.

To save lives and for the safety of everybody on this planet, we need to get the cost of the tests down and I think that we can do that. And by we, I mean all of us, but I also mean the people at Danaher and Cepheid who have worked hard on setting their pricing models and who I'm sure have lots of targets they've been asked to hit. And who absolutely can, I think, take a hard look at the spreadsheets and ask what's the right thing to do and how can we get the cost of a multi-drug resistant TB cartridge down to like $5. We are not enemies here, we are allies. The enemy is tuberculosis, so let's do it!

John, I'll see you on Tuesday.