Expert: Immune System Acts as a Perfect Analogy of Appropriate, Inappropriate Discrimination, Showing Disorder Discrimination Can Cause When It Runs Awry

Pharmacy Times® interviewed Steve Simske, PhD, professor of systems engineering in the Walter Scott, Jr. College of Engineering, Colorado State University (CSU), on his research investigating how the body’s naturally discriminating system, the immune system, may help to demonstrate appropriate and inappropriate discrimination between self and non-self outside of the body and in one’s environment.

Pharmacy Times®: How is discrimination a natural element of biology, and what are some subconscious ways humans use discrimination to get around in their day-to-day lives?

Steve Simske: So discrimination in biology is part of how we know whether or not something is part of us. So it's self or it's non-self, [the latter of] which is something that is an invader, like a virus or a bacteria, or any other type of pathogen.

We use that so that we know what to actually allow to be in the body because the body actually has more bacteria cells in it than it does eukaryotic or animal cells, because bacteria is somewhat smaller, there's more of them than there are actually human cells in your body. And a lot of bacteria are very helpful in digestion and prevention of other pathogens attacking the body, etc.

So we naturally discriminate, and that goes all the way back to the development of even the learned immune cells, the T cells and the B cells, which have a learned immune response, like you get a vaccine, and you'll be able to react then to that pathogen maybe decades later, because your body has what's called clonally deleted all of the cells that it thinks are ourself, and it's clonally selected the cells, T cells or B cells, that will attack something that's non self.

So discrimination at the front end for the immune system is a very helpful way for us to protect the body from things that can attack it, and not attack the body itself. Now, when we get to humans and look at the analogy there for discrimination, discrimination is something that we've used not in a bad sense, this is the good sense of discrimination, if you will, but discrimination is something that has allowed us to evolve and to separate ourselves from other walking, bipedal primates, etc, depending on how far back you go in time.

But all of us know, hey, if we're walking down a street at 3 in the morning, it's dark, it's pitch dark out there, we're naturally going to discriminate between the side of the street that has shadows on the side of the street that has street lights; there's nothing wrong with that. We naturally discriminate; it's part of what we use to basically gauge whether we make decision A, B, or C amongst those choices. And so that's the starting point for both of those is that we look at discrimination as a way for us to differentiate between good and bad, between dangerous, potentially dangerous, and less dangerous, etc. So that's the analogy between the immune system and what humans do for there, if you will, innately bias behavior. We don't really even think about it per se, we may be just doing something and say, ‘Oh, that's the right choice to make,’ or you look at the traffic ahead of you, and you see, it's completely backed up and you see an off ramp, and there's a side road you can take. So you make a choice there to discriminate between moving down the crowded highway and hoping that jam leads or taking the side road and hoping you can move around and on the side road, etc.

So those are just a couple of examples. It's a great question. But the starting point for discrimination is that we actually differentiate very simple things between making a choice A or choice B. And for our body, the choice may be A is self and B is non self, and it decides whether or not to have those cells that it thinks are non self-removed, or cells that it thinks are self stay there.

Pharmacy Times®: How does the human immune system’s natural discrimination between self and non-self potentially lead to problems when in excess?

Simske: Yeah, so that's a great question. What you're asking there is, how are the mechanisms for the immune system able to be fooled, if you will, by the difference between self and non self?

So a good example of that, I alluded to that in the answer to the first question, is something we call clonal deletion. Now, what works out in biology is that you end up with millions of potential B cell and T cell receptors. And these are the little claws, if you will, that attach on to the antigens, and allow us to remove antigens that are basically some type of a surface marker for an invader like a virus or a bacteria, and they lock onto that and then allow it to be removed from the body through some complicated processes such as opsonization, which I won't go into details here, but the bottom line is a to have that targeted for removal from the body because it's a pathogen.

Now, the immune system actually grows up inside of your bones in the bone marrow, and to some extent in lymph nodes, spleen, and thymus and other areas, but you'll notice none of those are behind the blood-brain barrier. So a simple example of an autoimmune disorder where your immune system accidentally, if you will, attacks yourself is multiple sclerosis. And that happens if there's a viral infection, for example, that allows some of the immune cells to get past the blood-brain barrier and be exposed to things like myelin, which is the sort of capacitive sheath that's placed around some of the nerves or tracks inside the brain, that would be tracks outside of the brain, nerves, in your body that allows it to speed up conduction so that we can react more quickly than being really slow, with our sensorimotor reactions.

So a lot of complicated terms there. But the simple thing is that your immune system has never been exposed to specific elements of your brain before. And so when it's exposed to that it thinks, because it hasn't been removed from the body, the cells that can attack myelin, they think myelin is something they should attack. And you end up with an attack on your own brain by your own immune system. And the brain and the immune system, the central nervous system of which the brain is the primary element, are our 2 principal systems of memory in the body. The brain, as we know, holds hundreds of billions of cells and many hundreds of trillions of connections between them. It's like a very large analog computer. But the immune system also holds memory of millions of different pathogens, potential pathogens that it can recognize, and many more millions that are also in common with the body that it deletes so that there aren't cells that do that.

So what's really cool about that is if you look at the analogy to what we're doing with a lot of brain based artificial intelligence, things like deep neural networks and convolutional neural networks, which are based on, in theory, the way the brain and central nervous system works, the immune system does both deep learning, where it learns things that are going to be pathogens for the body, and deep unlearning, where it learns things that are actually part of the body that it doesn't want to attack. In that way, you might actually say the immune system has a level of sophistication that many artificial neural networks don’t because it does both deep learning and deep unlearning.

Pharmacy Times®: How might the mind impact the body regarding discrimination of self and non-self, and vice versa?

Simske: One of the areas that this triggers off of is I was part of a program here at Colorado State University that is called the Faculty Institute for Inclusive Excellence. And they encourage us, if we have time and inclination, to create a project for that to get a fellowship. So I did that a couple of years ago, in 2020, and my fellowship was on drawing the analogy between what actually happens with discrimination in the immune system, and what happens for humans. As we talked about in the previous question, when you end up with an autoimmune disorder, it's where discrimination has actually gone awry.

We know as humans, we're thinking animals, we've got a big brain, relative to most animals, and you look at the weight, and all of the other things that go along with us carrying this big head and big brain around. It's a huge metabolic investment by humans. And so we look at this and we go, we are naturally given rewards for discriminating, we look at a plant, and we see those are actually rich berries that are going to give us all kinds of vitamins and other things, it's going to taste good, it's going to give us calories, versus this one over here, which is filled with toxins, and we know if we eat too many of those, we're either going to throw them up or potentially even die. So we are used to being rewarded for discrimination.

What happens is that we are as a species innately predisposed or pre-adapted to try to distinguish between A and B. And so it turns out, unfortunately, that really trivial things, genetically very trivial things, there's a much bigger difference genetically, between a binary male and a binary female, as there is between any two races of the same sex. And that's just a tiny little difference on chromosome 23 out of 23, the tiniest chromosome, a tiny difference there between male and females, that's far bigger than any difference between all of the superficial things that we see different between people.

But unfortunately, or fortunately, in some elements, the fortunate part is that our ability to discriminate also means that we can discriminate between good and bad discrimination. But I'm getting ahead of myself.

The unfortunate part is that we are predisposed to discriminate based on relatively from a genetic or certainly personality standpoint, trivial difference between 2 people. And so the fortunate part is that that built in discrimination can then help to overcome that, because we can recognize when we're using appropriate discrimination when we aren't, again, appropriate discrimination, choosing to go down a lighted street versus, oh, I think I'll go into a manhole and walk down the sewer instead of going through the street, and maybe that'll be safer, right? That would be insane. So we know that humans have that ability to use discrimination for reasonable outputs. We also have again, that predisposition to look at really trivial differences—height, age, gender, sex, skin color, all of these things that people end up having some unfortunate innate biases towards, those innate biases are there evolutionarily. So recognizing those and realizing that we do make some discriminations there that are inappropriate, both in our real life and in the immune system, as we pointed out for the autoimmune disorder, that is actually the basis of my fellowship with CSU.

Pharmacy Times®: Have you published your research on this subject yet or is your research ongoing currently?

Simske: So that's ongoing, what we're actually encouraged to do is keep in mind, the university first and foremost is about its students. One of the reasons I'm at Colorado State—I've had other careers working with NASA and working at a large electronics and consumer electronics company—one of the reasons I'm here is because Colorado State really values the education that it's giving students and really, you can't have a university without students. You might as well have like a government agency, like Los Alamos do great research or, as I did at Hewlett Packard labs working on great research there for specific products.

With CSU, they're really encouraging it to roll back to the students and to find natural, non-cringy ways to integrate this type of information into our courses. So right now, I'm building a course for our systems engineering, and over half of our students are in the aerospace industry, so I've been asked to put together a spaceflight life sciences or spaceflight biology class, because I used to do a lot of work in that space. And what I've done is actually integrated the fellowship directly into the immune lecture.

So the key thing there is to make sure students recognize this is not a timeout, this is not something that's just an add on, this is not like a little appendage, like an appendix, on the body that we don't actually need, but make it core to and integral to the actual lecture you're giving. So in the immune system lecture, which I'm actually just putting together now to start the class in the spring, the part that I was talking about, the analogy between how we discriminate as humans and how we discriminate with our immune system is actually the anchor of the immune system lecture. It's a great way to show people how immune discrimination works ending up with, unfortunately, many auto immunities, I listed multiple sclerosis, but we have Graves’ disease, we have lupus, we have a whole host of rheumatoid arthritis, there's a whole host of other immune disorders that are familiar to most people as well. So really, the key thing there is to integrate it into the curriculum and make it fit in there naturally. That's one of the things that I've been very pleased with CSU is that each of my classes has a way to bring equity, diversity, or inclusivity, in naturally without forcing it.

The other element of that, and I think you sort of alluded to this with your good question, is that we look at this and say, hey, is there actually a way to put this in curriculum without triggering negative or defensive response from people. When you talk about the discrimination in the immune system, it's completely agnostic. I mean, nobody, we're not talking about whether self or non self is ageism, or racism, or sexism, or genderism, or ableism, or wealthism—any of those types of things are left out of the discussion; people can interpret it how they were, and so we don't leave out people who are potentially getting triggered by it.

That leads to another very important point here is that a lot of times when you're talking about good topics like DEISJ all the way through social justice, one of the problems is that you're often preaching to the choir, if I may use that expression. In other words, the people who are coming to those meetings are already predisposed to be looking for social justice in the things they're doing.

What we really want to do is reach out to the other side, have that conversation, include them in the conversation so that we can get their perspective on that. And that's, of course, a very important thing to do, as we see society polarizing in so many ways right now. So the big motivator behind that fellowship, and behind that part of my curriculum is to make sure everybody can be part of the conversation, and they don't have to feel like it's directly addressing whatever innate biases they may or may not have.

Pharmacy Times®: At Colorado State University, you work in the College of Engineering. Does this biomedical research apply in that field as well?

Simske: One of the things that we look at when we look at the effect of spaceflight and microgravity, there's stress, there's fatigue, there's all these other factors, all these things and claustrophobia and nihilophobia, which is the fear of nothingness. I mean, if you're out driving your car and it breaks down, you're like, oh, I'm on land, somewhere, I park on the side of the road, again, my tools out of the back, hopefully can fix it. If not, I call a tow truck. In space, if it breaks down, there's nothing around you. So you actually have this fear of emptiness around you. It's really kind of a different environment.

So all of these things are going on, and we say, how do we isolate the effects of different elements of that environment on the body. And when you get to like the musculoskeletal system, so your arm deteriorates, because it doesn't get weighted loading, that's pretty straightforward, we have that connection between the cardiovascular system, if you're six feet tall, you've got about 140 millimeters of mercury pressure difference between the top of your head and the bottom of your feet, that's higher than the systolic or diastolic pressure. So it dominates what's going on Earth, this gradient that we've got, that disappears in space.

So those are very easy connections to make between the physiology and the effects of microgravity. When we get to the immune system, everything's out the window, because it ties into everything else. And so the immune system is this naturally distributed environment. You've got immune system elements inside of most of your bones that, particularly like the ribs, and the more central bones, the spine, etc, but all of your long bones as well. The immune system itself is in the lymph nodes, it's in the spleen, it's in the thymus, it's distributed around the body, it's carried around by the cardiovascular system in the blood, about one out of every 700 cells in your blood are white blood cells that are there for a wide variety of immune purposes. And so the natural part of the curriculum is to restart to recognize there's a lot of shades of gray when we get to the immune system anyway, just like there's a lot of shades of gray when we start talking about the positives and the negatives of discrimination both in the immune cell. And then by analogy, whatever else the student wants to internalize.

So I think it's a very core part of the curriculum, it fits in easily with the description that we have, for how the immune system works, and how the immune system is affected by something as equally dispersed as spaceflight. Again, as I mentioned, you've got noise, you've got fatigue, you've got stress, you've got radiation, you've got unloading, you've got fluid redistribution, all of these things going on in spaceflight. That's a lot that that can blow your mind, when you start to think about all those possible interactions between those. And so we start talking about, functionally, what works. So we measure whether or not the immune system is able to prevent viral infections, is it able to prevent specific ailments from starting in those people who are exposed to spaceflight, and then we start to say, hey, there's an analogy there between the functional aspects of discrimination, does discrimination work for good? I walk under street lights at night, and I don't get mugged, right? That that's a good discrimination. Or if I start to discriminate, and I end up hiring 50 people who all look, think, and have the same background as me, that's clearly a dark side. Right? So we look at those things, and we say there are functional surface measurements that we can make that tell us about the health of the immune system, or the discrimination system underneath it. And I think that's a really important element. And that is actually the lecture that shifts us from being able to have some more direct causal relationships between spaceflight and the deleterious or negative effects on the body. And once we're, we're not clear what the direct correlation is, but we just know whether it's working or not.

I think that's in the world we live in, that's really where we have to go with ending inappropriate discrimination, we need to look at what are the functional aspects of what we're doing, are they healthy overall, or are they non salubrious overall.

Pharmacy Times®: How does your background in engineering help you to think about this issue in potentially a different way?

Simske: Yeah, good question. Well, I have a biomed background, ao it's a straightforward jump for me. But, overall, systems engineering is really analogous to biomedical engineering I think of biomedical engineering as systems engineering applied to living things. So you have to account for things like biocompatibility, all of the health issues and safety issues that are for humans. But as a systems engineer, your systems also have to be safe, they have to be cyber secure, you have to have a data plan for them, a sustainability plan, all of those things go with it. So there's a direct analogy there. And from a systems engineering standpoint, where you start to look at how all of the different modules of systems come together, how they interface and what relative transfer functions or effects that they have on each other. Those are directly relevant towards looking at the biological element of it.

So I think it's a pretty natural fit. And I think the use of analogy and allegory I think is very helpful to people because it also predisposes them to thinking of something I wouldn't have thought have, as the facilitator for that particular information. I mean, there may be a student of mine who comes along and says, hey, I have a much better analogy for immune system discrimination, that doesn't even tie to this types of discrimination you're talking about, but it talks to maybe some type of bias people have in performing actions that leads to lack of safety. And they might end up with a direct analogy between that and safety that I hadn't thought about, or sustainability or cybersecurity. And it's like, that's the whole point of it. If I'm in a room with 30, students, there's 30 times the brainpower in those students than I have in facilitating the discussion. And so I think, really, what you want to do is get to this point where education is metacognitive, where we're actually teaching people how to learn, because, again, the specifics of anything, they can go and learn on Udemy or on Coursera, or in other places in 100 or 200 level courses that lead them up to it. What we're trying to do in graduate programs is get them to be thinkers about thinking so that they can help other people learn how to learn etcetera. And that's really where we go.

I think you know this as well as I do, I mean, we're moving towards a situation in the world where we have a lifelong learning, there's things that change so fast that your education basically needs to be refreshed every 7 years for you really to stay current with where everything is. And so this, I think, is fundamentally part of that sort of recognition of where education is going in the future.

Pharmacy Times®: What can we learn from the body regarding when discrimination is helpful and when it is unhelpful?

Simske: Well, fortunately, the body, just like we all know some angry people, just like those people, gets inflamed when it's using inappropriate discrimination. We can actually see that the brain has inflammation, it's a specific process where there's an invasion by granulocytes such as neutrophils and activation of mast cells and dendritic cells, etc. I'm not going to go into all the details, but there are some specifics behind that. It's called inflammation for a reason. People take antihistamines or aspirin or whatever else—acetaminophen—to try to reduce that inflammation because it can be negative. So we have a direct analogy there. It's not a forced fit.