Frameworks of Cellular Pathology

00:01 Hello, and welcome. We are going to now explore the beautiful world of pathology and for those of you who don't think it's beautiful, you just haven't learned the right way to think about it.

00:12 In this first set of topic discussions, we're gonna look at just general broad concepts.

00:19 This will hopefully give you a framework for thinking about how disease happens and give you a way for thinking from first principles about any disease process at any tissue.

00:32 It's really beyond this first topic, it's all just details.

00:37 Now, the details are really interesting and we're gonna have a great time talking about them.

00:41 But this first, this first discussion gives you a way to think or a way that I think.

00:48 So, broad concepts and paradigms.

00:51 Disease, when it comes right down to it, is really a combination between your genetics and what the environment does to you and how they interact and that's really all it is.

01:05 Some people will have no response to particular environmental influence.

01:11 So, there are people who can smoke like a chimney for 100 years and never have a problem and there are others with the same environmental insult, cigarette smoking, will develop severe atherosclerosis or lung cancer at a relatively early age.

01:29 So, it's the genetics and the environmental factors happening together.

01:34 When we have cell or tissue injury, there are kind of two outcomes.

01:40 You either adapt or you die and when I say you, I'm talking about cells and tissues but also, the organism.

01:48 You either develop an adaptation, a response that allows you to have that cell tissue organism continue to survive or you die.

01:59 Harsh but true. In the human body, actually, in every cell on the planet, "everything" is constantly renewing. It's constantly turning over.

02:15 We do not synthesize a membrane or an organelle or a cell or a matrix once and it's good there forever.

02:23 It's constantly being renewed.

02:25 That's an important concept because that renewal, that renewal process is not always perfectly perfect.

02:35 There isn't perfect fidelity and every now and then, we accumulate a little change, a little mutation, a little something different.

02:43 So, everything is constantly renewing and except, sometimes, it's not as we'll see some cells, some tissues do not renew at the same rate, so, or not.

02:55 And again, in senescence as we age, the renewal process is not as good.

03:03 It is not as robust. So, yes, everything is constantly turning over.

03:07 Every membrane, every organelle constantly turning over but there's a limit and that limit is called, I guess, the end of life.

03:17 The other thing that's always going on from the environment, we're constantly under attack.

03:23 Well, what do I mean by that? Well, in fact, oxygen, oh my God, oxygen, that's attacking us? Well, yes, because we have evolved to breathe 21% oxygen and to extract energy through the oxidative phosphorylation pathway using that percentage of oxygen.

03:42 If I put you in a hyperbaric chamber at 100% oxygen for a week, your lung will begin to fibrose because of injury from reactive oxygen species.

03:54 Glucose, what? That's a bad thing? Well, no, not necessarily but in higher concentrations, too much glucose, hyperglycemia, well, that's diabetes and that does cause pathology.

04:10 So, even things we think as being imperfectly physiologic can under the appropriate circumstances cause damage and then, there are always the toxins and not just poisons from underneath your sink but there is a lot of potentially injurious material that's out there in the world that is constantly bombarding us.

04:34 We're eating it, we're breathing it, we're rubbing it in our skins.

04:38 Infections, they're everywhere. From viruses through bacteria to fungus to parasites and they are constantly there in our environment unless you are a boy in a bubble someplace, you are subject to constant attack by various infectious agents and we need to deal with that.

05:00 Radiation, we're walking around, we're being bombarded by gamma radiation.

05:04 If you go into our basements, we're getting radon.

05:07 So, radiation injury is constantly there too and we need to respond to that.

05:12 UV light, just walking out in the sunlight, there are elements, there are wavelengths of UV light that are causing DNA damage.

05:21 So, from a variety of things, including things we think are just awesomely good all the time, oxygen and glucose, we are constantly under attack.

05:30 So, then, a result of all this is one of the three laws of thermodynamics, entropy always increases and it's no different for a biological system. Yes, biology fights against this.

05:43 We have mechanisms that allow us to be around a lot longer that we don't randomly fall apart but as Paul Simon said in his song, everything put together sooner or later falls apart and as I'd mentioned previously as we're constantly renewing, there's not perfect fidelity unfortunately and overtime and hopefully over 100 years for most of us, we eventually accumulate small, little papercuts of life that will sooner or later lead to senescence of a cell of a tissue of the organism. Tissues are not created equal.

06:23 So, an injury that is in one tissue may be relatively unremarkable and other tissues could be lethal.

06:32 So, if you just think about it, if I had a little tiny pimple on my skin, a little area of infection, "Okay, fine, I'll treat it with a little antibiotics." A little pimple or equivalent in my brain might actually be potentially lethal.

06:46 It might lead to me losing a memory or not being able to move.

06:51 So, location, location, location. Not only that, some tissues can regenerate.

06:56 Some tissues like bone marrow, constantly creating new bone marrow from stem cells all the time.

07:01 Skin, lots and lots of skin all the time.

07:04 GI track, the lining of the GI track constantly renewing. Heart, nope.

07:09 Once you build a heart, those cells, if they're damaged, don't regenerate.

07:14 Same thing with neurons. They don't regenerate. So, tissues are not created equal.

07:17 So, when injury happens in a particular site, you have to take into context of what's being injured.

07:24 In biology and in medicine, a really important concept and I will highlight this over and over again when it occurs. But for every pro, there is an anti.

07:37 There is an equal, sometimes an opposite reaction. What is -- what do I mean by that? Well, for example, cells are constantly turning over.

07:45 So, they're proliferating. Well, we're not clearly getting bigger and bigger, and bigger.

07:49 So, that means it's cells at the same time they're proliferating, other cells are dying.

07:54 So, there is a proliferative and an anti-proliferative equal and opposite reaction.

07:59 And in inflammation, there is a pro-inflammatory process.

08:02 If that's happening, you can bet there's an anti-inflammatory process also happening concurrently to kind of fine tune that.

08:11 And if something is pro-coagulant, tends to form clotting, there's gotta be a pathway that's anticoagulant.

08:17 So, there are always opposite reactions and we have to be aware of that because otherwise, if it was just a one-way street, we'd be in trouble.

08:25 Processes in the human body tend to occur in amplifying cascades.

08:30 So, a little spark someplace will not do much but will now spark the next things next to it and then, they will react with the next things and the next things, and the next things that pretty soon, we have something that we can recognize as a response but an individual cell or an individual factor all by itself doesn't do much.

08:50 So, we have to have ways in the human body, in any body, to get from an initial stimulus to something that is a largescale action and that happens in amplifying cascades.

09:03 The human body is over-engineered and that's a good thing because we have, you know, I can take out one lung, I can still live with just one lung.

09:14 So, we're -- we are over-engineered but many of the pathways that we're gonna talk about are not just the pathway.

09:22 In fact, it gets so complex that it can be mind-numbing and you just roll your eyes and you say, "Too many pathways." Well, that's good because there are many different ways that we can get from one to another and we're gonna see a lot of redundancy.

09:38 This is important because if one pathway is redundant with another pathway, if I knock this one out, that one still works.

09:45 But if I give a drug that only blocks that one, I haven't had any benefit.

09:49 So, understanding that redundancy is important.

09:53 Pathways are also promiscuous. What do I mean by that? Well, you think that some factor is involved in driving proliferation.

10:02 Well, that factor is also important in driving new blood vessel formation or that factor is important in driving scarring or that factor is also driving something else.

10:13 So, it's not one thing doing one thing.

10:18 There are many things that do the same activity and one thing can do many activities.

10:24 So, it makes it interesting. It makes it more complex but we embrace that.

10:30 In general, it's not just the disease. It's not just the injury and the genetics but it's how the body responds to it.

10:40 So, earlier on, I said, "You adapt or you die." Well, okay, that's a little harsh but if you have an infection and you don't respond to it and that infection is not particularly lethal or lytic, doesn't kill cells, you can live with that.

10:56 So, hepatitis B, a great example.

10:59 There are 10% of the population who gets exposed to hepatitis B who walk around with it and never have a problem with it.

11:06 That's because their immune system doesn't recognize that hepatitis B.

11:11 They're just carriers and they can live happily ever after.

11:14 You only get the disease hepatitis once the immune system goes, "Wait, there's an infection there in the liver." So, it's not just the disease. It's what the -- how the body responds to it and what you do with it.

11:26 We will talk about a lot of various topics and that's what I'm here for.

11:36 We will and I will refer to a number of experimental models that allow us to understand what's going on and we frequently use little mice.

11:46 We frequently use worms and fruit flies and everything else.

11:50 It's important to know that the models and the information that we get from them need to be taken with a little bit of a grain of salt.

11:58 Models make a difference and really, truly for example.

12:01 Mice just are not furry little humans.

12:04 They have different enzyme activities. They've got different responses.

12:08 And so, for example, in many cases, we've cured cancer 100 times in mice and clearly, we haven't reliably cured cancer in humans.

12:17 So, the models will make a difference and where that's important, I'll point it out.

12:21 And in vivo veritas. So, for the Latin scholars following along, in life is truth and in vivo basically means in the body intact.

12:34 We can have test tube models. We can have petri dish models, we can have animal models but really, if you want to understand human disease, you have to understand human disease in the humans that have it.

12:46 So, that's really going to be the final reality check when we are talking about the various models.