This SciShow video is supported by Linode!

Go to linode.com/scishow for a $100 60-day credit on a new Linode account. What if we were able to create a needle so small it could inject a protein directly into a single cell?

That would be a huge leap forward for vaccine technology, because one way our immune cells learn to recognize enemies is by their proteins. And getting proteins inside cells is really tricky. Believe it or not, the microneedle in question may soon be possible.

But it isn't made by a medical device company. It's made by a kind of organism we often think of as making us sick: bacteria. [ ♪ Intro ♪] There are lots of things that can make us sick, and most of them are really small. We know of more than a thousand microbe pathogens, including viruses, bacteria and fungi.

The immune system does a decent job of fighting invaders, but prior exposure or getting vaccinated certainly helps it work more efficiently. It’s like being able to study for a test rather than taking a pop quiz. Proteins that can induce an immune response are called antigens, and if your immune cells get stable, intact protein antigens to work with before an infection, they’re able to mount a better immune response to things like viruses and bacteria.

Scientists have a few strategies for developing vaccines to do this, including using killed or weakened microbes to prep the immune system for live versions of those pathogens. More recently, they’ve developed mRNA vaccines that provide instructions to cells on how to make antigens themselves . But here’s the problem, and why making good vaccines is so challenging: it’s really difficult to deliver protein antigens or mRNA directly into the immune cells that can use them to marshal defenses.

The problem is twofold. First, targeting immune cells means your delivery system has to be able to recognize immune cells. Second, proteins or mRNA have to get past the cell membrane, a lipid layer that allows cells to be really selective about what they take in from the environment.

If we had a way to inject a vaccine directly inside immune cells, we could vastly improve the number of them with the antigens they need to fight a particular kind of infection. And infections aren’t the only problem that direct protein delivery could solve. It could also help with treating diseased cells.

A lot can go wrong inside human cells that doesn’t involve viruses or bacteria. Cancer, for example. Direct protein delivery would not only enable us to inject cancer vaccines into immune cells, it could also help deliver special blocking proteins into the cancer cells themselves.

These blocking proteins, called nanobodies, bind to and neutralize malfunctioning proteins, like those commonly found in tumor cells. So ideally, we’d need a syringe that can identify and target particular types of cells, and deliver protein directly inside . Which seems like it would require a needle so small it’s hard to imagine.

But as luck would have it, some species of bacteria have just that. Using a microscopic harpoon-like structure, they inject their enemies with toxic proteins as part of their natural defense systems. Typically, they do this to other bacteria, fungi, or amoeba.

But there are several varieties of these weapons, called secretion systems, and some have evolved to inject proteins into human cells to defend themselves against an immune response. Recently, scientists have been studying how we might use these weapons in our favor. It’s possible to modify these bacteria t o inject useful proteins inside human immune cells.

But there are other ways of making vaccines, so why would we want to use bacteria? Well, they multiply rapidly, which means they could provide us with self-manufacturing vaccines. Since bacteria make the proteins fresh for delivery, there’s no need to isolate and purify antigens, which would be expensive and time-consuming.

The antigens are protected from degradation too, because they’re stable inside the bacteria until they get syringed into immune cells. And immune cells seek microbes, so bacteria are a great way of delivering antigens directly to them for vaccines. But hijacking bacteria to make them into syringes isn’t easy.

First, scientists have to make the bacteria safe by making the infectious microbe not infectious. This process, called attenuation, basically means modifying it so that any natural toxins are removed. Attenuation can also involve making sure the bacteria can’t reproduce, to limit how long they can stick around in the body.

Then scientists add DNA into the bacteria, instructing them to make new, useful proteins. They also need to add special tags to the proteins, so the bacteria gets the instruction to secrete them, not just make them and hold onto them.. This research is already underway.

Bacterial secretion systems have been used to deliver a variety of antigens into immune cells, and there’s even preliminary work on utilizing them for a new COVID-19 vaccine. We can even use bacteria to fight bacteria, in the sense that good bacteria can deliver the antigens of bad bacteria to our immune cells, putting them on guard against infection. There are several vaccines in development like this that target the bacterium Listeria monocytogenes, which is the third-leading cause of death from food-poisoning in the US.

On the cancer side of things, a bacteria-based vaccine that prepares immune cells to attack multiple myeloma begins Phase One clinical trials later this year. As for injecting cancer cells themselves, a study published in 2013 describes the use of attenuated E. coli to secrete nanobodies into breast cancer cells in mice. These blocking proteins were able to reduce tumor metastasis by interfering with a protein that was over-expressed in the cancer cells.

And weirdly enough, Salmonella bacteria are attracted to tumors. There’s already been a lot of research on their secretion systems, so Salmonella could be a good candidate for fighting cancer cells. Just … not before they modify that Salmonella to be harmless.

So even though there are a lot of dangerous bacteria out there, their ability to deliver proteins inside cells could be a huge benefit to us. Someday soon, you might get medicine delivered right to the source of the problem by a bacterium with a tiny needle. Thanks for watching this SciShow video, supported by Linode!

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