Listen: How Immunity Works

Zombies, villagers, and Navy SEALs. An immunologist explains the immune system.

On this episode of the podcast Social Distance, Katherine Wells gets the results of her coronavirus and antibody tests. She has questions about what they mean, so an expert joins to explain the immune system (with help from James Hamblin’s metaphors).

Lisa Butterfield is a tumor immunologist who works in cancer immunotherapy. She’s the vice president of research and development at the Parker Institute for Cancer Immunotherapy and an adjunct professor at UC San Francisco.

Listen to their conversation here:

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What follows is an edited and condensed transcript of their conversation.

Katherine Wells: Are you the type of scientist who always figured a pandemic was around the corner, or are you the type that really never thought it could get to this level?

Lisa Butterfield: I’m not surprised, given the signals we’ve seen from around the globe where humans have increasingly encroached on natural areas and are exposed to more things that are able to jump species. I watch a lot of zombie movies, so I’m just relieved it’s not the zombie apocalypse yet.

James Hamblin: Some of the only exposure to the idea of what a pandemic could look like had come through movies like Contagion and Outbreak. Transitioning to immunology: COVID-19 can affect people in so many different ways because people’s immune responses vary in so many different ways.

Butterfield: Absolutely. You and I could have five times different numbers of T cells—white blood cells in the circulation—and be perfectly healthy. There is enormous variation.

Wells: Could you give me as simple as possible an explanation of how the immune system works?

Hamblin: Can you explain ... the solar system?

Butterfield: Yeah, the immune system is beautiful in its complexity and specificity. That makes it challenging to talk about in any detail. We also love our jargon in immunology.

The immune system is there to protect us from infection and the things we encounter in the environment. There are cells and molecules in the blood that are ready to immediately react when they detect something. And then the more specific part of the immune system takes about a week to ramp up. So that’s why you might get sick first but then you clear the infection.

Hamblin: I’ve used this metaphor before that you have this innate immediate response, and it’s like the townsfolk grabbing their pitchforks and torches and immediately responding to this invasion. And then about a week later, you have the Navy SEALs, who were really efficient at fighting some invasion. They come later, but they hang out afterward.

Wells: The antibodies are the week-later response, is that right?

Butterfield: Yes. That’s the specific response of the Navy SEALs that shows up a week later, when the immune system starts to see what’s going on. It harnesses two other parts of that specific immune system, the T cell and the B cell. The B cell makes the antibodies—and those are proteins floating around the blood, looking for that thing that they’re specific to. Our hope for the antibody part is that they’ll stick to the outside of the virus and block that part that interacts with the rest of the body that allows the infection to take place. And so we’ve got neutralizing antibodies. We neutralize the infection and the ability for the virus to get into any of the other cells in the body.

Hamblin: That might sound like jargon to some people. It’s really important that everyone understands that you can have antibodies that bind to a virus that are not neutralizing and the virus is still able to bind to your body cells and do harm. And then you can have neutralizing antibodies like you’re discussing. And those are supereffective. And that is our hope, that that is what we are seeing in the antibody tests. There are diseases like HIV where you have antibodies but you don’t clear the virus. If they are Navy SEALs, sometimes the virus just sort of has, like, bullet-proof armor … I guess you could say it’s an invader like a zombie or something. And the Navy SEALs just cannot neutralize this thing.

Butterfield: Yeah. They fire all their bullets and it keeps coming.

Wells: I got an antibody test recently and it came back negative. Does that mean I don’t have the neutralizing antibodies?

Butterfield: If the test was conducted properly, it answered the question it asked. And it may have asked the total antibodies: Has your body seen this virus and had an antibody response of any kind? Or it could have specifically asked: If you saw the virus, did you come up with that really effective antibody response? Most of the tests I’m aware of ask the total-antibody question.

Hamblin: What’s your sense right now about how likely it is that those would be neutralizing antibodies?

Butterfield: The data I’m aware of thus far says that if you have positive total antibodies, that some of those antibodies really will be the good, neutralizing, effective antibodies. Then the question is: How much? Are there enough of them? And are they going to hang around long enough to protect you? And that’s the next part of the mystery we have to solve.

Wells: When do we think we could say, Okay, having antibodies at this level actually means you’re immune?

Butterfield: Well, hospitals and universities and different companies are testing [for antibodies] all the time. And if our hope is that antibodies could protect you for a year, kind of like an influenza vaccine is thought to protect you for that year’s flu, then we’re a year from starting to collect the data to having so much exposure opportunity that we think we have an answer.

Wells: I’ve been reading about the idea that you lose these antibodies over time. What does that mean?

Butterfield: The data showed that there is a decline in what was measured over time. And that’s normal, to an extent. The immune system regulates itself. In an infection, you’ve got those early responders—the villagers with pitchforks trying to stop something initially. Then the Navy SEALs came in after a week and they really specifically targeted exactly what the problem was.

And then the problem goes away, the infection goes away. The villagers already went back to their lives when the Navy SEALs showed up. And now the Navy SEALs go back to headquarters and wait for the next problem, and the village goes back to normal life. You might leave a couple Navy SEALs there just in case.

Wells: What is the mystery of coronavirus to you, as someone who thinks about this all the time?

Butterfield: The thing I worry about the most are long-term effects of the virus, which we’re just starting to see. I was hoping, like all of us were hoping, that it was going to be a bit more analogous to an upper-respiratory tract infection, where it would stay in one place, do one thing, and be cleared. And that’s not how this is going. This is affecting a lot of different organ systems and it’s leaving people with residual effects even after they’ve gotten rid of all signs of the virus.

Hamblin: So, in the metaphor, when you deploy the military into a small village to defend it, the deployment itself can create issues. It might be overall good. You want the Navy SEALs in there. But it’s obviously a very difficult thing to do.

Butterfield: The Navy SEALs come in and some buildings get blown up, but the buildings can be rebuilt. Part of it is taking time to rebuild the buildings. You’ve got some tissue destruction and you can heal yourself. But then, years later, you realize that all the bombs and things made the ground toxic.

Hamblin: You’ve created some zombies, possibly.

Wells: Oh my God, this is really scary. Just to clarify one thing about these tests: The test results for antibodies are not testing for T cells, which could actually have some Navy SEAL–like properties?

Butterfield: Correct. First we had to figure out how to identify the virus-specific T cell: Which Navy SEAL was looking for the virus and not looking for something else? We can now do that in a number of cases.

Hamblin: That’s a bit of hope, right? People were seeing these antibodies waning and starting to panic. And what you’re saying is: That’s not the only part of the puzzle. There are other things that could help a person, even if antibodies wane.

Butterfield: Absolutely. That’s part of the excitement about some of these early data from the vaccines, because these vaccines are designed to both create antibodies and to activate killer T cells. That’s something we’ve learned along the way: how to activate both types of immune response at the same time, antibodies and T cells. I think we can do that with these vaccines. We don’t know how good or how effective yet, but it’s very encouraging they can do both.

That’s going to be good and that’s going to stop some of the damage. So there won’t be all of those munitions poisoning the ground and all of the homes blown up. There’ll be a couple select homes that go because that’s where all the virus was, and then maybe the Navy SEALs will leave earlier and we won’t have as much to rebuild.

Hamblin: Just a few zombies wandering in and out occasionally.

Butterfield: One or two, but, you know, they’re okay.

Hamblin: Oh, that’s just Steve. He’s undead, but he’s no harm.

Wells: I’m going to have the worst nightmare of my life tonight.