Crash Course Biology Cancer Assignment

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Hank: It's just beautiful, isn't it? It's, it's just, it's, it's mesmerizing. It's, it's double hel-exciting. You really can tell just by looking at it how sort of important and amazing it is. It's pretty much the most complicated molecule that exists, and potentially the most important one. It's so complex that we didn't even know for sure what it looked like until about sixty years ago. So multifariously awesome that if you took all of it from just one of our cells and untangled it, it would be taller than me. Now consider that there are probably 50 trillion cells in my body right now, laid end-to-end, the DNA in those cells would stretch to the sun, not once, but 600 times. Mind blown, yet? Hey, you wanna make one?

[intro music]

Of course you know, I'm talking about deoxyribonucleic acid, known to its friends as DNA. DNA is what stores our genetic instructions, the information that programs all of our cell's activities. It's a 6 billion letter code that provides the assembly instructions for everything that you are, and it does the same thing for pretty much every other living thing.

I'm gonna go out on a limb here, and assume that you are a human, in which case every body cell that you have, or somatic cell in you has 46 chromosomes, each containing one big DNA molecule. These chromosomes are packed together tightly with proteins in the nucleus of the cell.


​DNA is a nucleic acid, and so is its cousin, which we'll also be talking about, ribonucleic acid, or RNA. Now, if you can make your mind do this, remember all the way back to episode 3 where we talked about all of the important biological molecules: carbohydrates, lipids and proteins, that ring a bell? Well nucleic acids are the fourth major group of biological molecules, and for my money, they have the most complicated job of all.


Structurally, they're polymers, which means that each one is made up of many small, repeating molecular units. In DNA, these small units are called nucleotides, link them together and you have yourself a polynucleotide. Now before we actually put these tiny parts together to build a DNA molecule like some microscopic piece of IKEA furniture, let's first take a look at what makes up each nucleotide.


We're gonna need three things: One, a five carbon sugar molecule. Two, a phosphate group and three, one of four nitrogen bases. DNA gets the first part of its name from our first ingredient, the sugar molecule, which is called deoxyribose, but all the really significant stuff, the genetic coding that makes you you, is found among the four nitrogenous bases: adenine, thymine, cytosine, and guanine.

It's important to note that in living organisms, DNA doesn't exist as a single polynucleotide molecule, but rather a pair of molecules that are held tightly together. They're like an intertwined, microscopic, double spiral staircase. Basically, just a ladder, but twisted. The famous 'Double Helix'. And like any good structure, we have to have a main support. In DNA, the sugars and phosphates bond together to form twin backbones. These sugar-phosphate bonds run down each side of the helix but, chemically, in opposite directions. In other words, if you look at each of the sugar-phosphate backbones, you'll see that one appears to be upside-down in relation to the other. 

(3:05) One strand begins at the top with the first phosphate connected to the sugar molecule's 5th carbon and then ending where the next phosphate would go, with a free end at the sugar's 3rd carbon. This creates a pattern called 5' (5 prime) and 3' (3 prime). I've always thought of the deoxyribose with an arrow, with the oxygen as a point. It always 'points' from 3' to 5'.

Now on the other strand, it's exactly the opposite. It begins up top with a free end at the sugar's 3rd carbon and the phosphates connect to the sugar's 5th carbons all the way down. And it ends at the bottom with a phosphate. And you've probably figures this out already, but this is called the 3' to 5' direction. Now it is time to make ourselves one of these famous double helices. 


These two long chains are linked together by the nitrogenous bases via relatively weak hydrogen bonds. But they can't be just any pair of nitrogenous bases. Thankfully, when it comes to figuring out what part goes where, all you have to do is remember that if one nucleotide has an adenine case (A), only thymine (T) can be its counterpart (A-T). Likewise, guanine (G) can only bond with cytosine (C) (G-C). These bonded nitrogenous bases are called base pairs. The G-C pairing has three hydrogen bonds, making it slightly stronger than the A-T base-pair, which only has two. 


It's the order of these four nucleobases of the Base Sequence that allows your DNA to create you. So AGGTCCATG means something completely different as a base sequence than, say, TTCAGTCG. 

Human chromosome 1, the largest of all of our chromosomes, contains a single molecule of  DNA with 247 million base pairs. If you printed all of the letters of chromosome 1 into a book, it would be about 200, 000 pages long. And each of your somatic cells has 46 DNA molecules tightly packed into its nucleus - that's one for each of your chromosomes. Put al 46 molecules together and we're talking about roughly 6 billion base pairs, in every cell!

This is the longest book that I've ever read. It's about 1, 000 pages long. If we were to fill it with our DNA sequence, we'd need about 10, 000 of them to fit our entire genome. 


POP QUIZ! Let's test your skills using a very short strand of DNA. I'll give you one base sequence - you give me the base sequence that appears on the other strand. Okay, here goes.

So we've got a 5' - AGGTCCG - 3' and ahhh, time's up. The answer is 3' - TCCAGGC - 5'. See how that works? It's not super complicated. Since each nitrogenous base only has one counterpart, you can use one base sequence to predict what its matching sequence is going to look like. 


So could I make the same base sequence with a strand of that 'other' nucleic acid, RNA? No, you could not.

(Three Differences from DNA) (5:43)
RNA is certainly similar to its cousin DNA - it has a sugar-phosphate backbone with nucleotide bases attached to it. But there are THREE major differences: 

1. RNA is a single-stranded molecule - no double helix here. 
2. The sugar in RNA is ribose which has one more oxygen atom than deoxyribose, hence the whole starting with an R instead of a D thing. 
And finally, RNA does not contain thymine. Its fourth nucleotide is the base uracil, so it bonds with adenine instead. 

RNA is super important in the production of our proteins, and you'll see later that it has a crucial role in the replication of DNA. But first...


(Biolo-graphy music plays)
Biolo-graphies! Yes, plural this week! Because when you start talking about something as multitudinously awesome and elegant as DNA, you have to wonder: Just Who figured all of this stuff out? And how BIG was their brain? 

Well, unsurprisingly, it actually took a lot of different brains, in a lot of different countries and nearly a hundred years of thinking to do it. The names you will usually hear when someone asks who discovered DNA are James Watson and Francis Crick, but that's BUNK. They did not discover DNA. Nor did they discover that DNA contained genetic information. DNA itself was discovered in 1869 by a Swiss biologist named Friedrich Miescher. His deal was studying white blood cells. And he got those white blood cells in the most horrible way you could possibly imagine, from collecting used bandages from a nearby hospital. (Laughs) Guh- It's for science he did it!

He bathed the cells in warm alcohol to remove the lipids, then he set enzymes loose on them to digest the proteins. What was left, after all of that, was this snotty gray stuff that he knew must be some new kind of biological substance. He called it nuclein, what was later to become known as nucleic acid. But Miescher didn't know what its role was or what it looked like.

One of the scientists who helped figure that out was Rosalind Franklin, a young biophysicist in London nearly a hundred years later. Using a technique called x-ray diffraction, Franklin may have been the first to confirm the helical structure of DNA. She also figured out that the sugar-phosphate backbone existed on the outside of the structure. So why is Rosalind Franklin not exactly a household name? Well, two reasons. 

1. Unlike Watson & Crick, Franklin was happy to share data with her rivals. It was Franklin who informed Watson & Crick that an earlier theory of a triple-helix structure was not possible and in doing so she indicated that DNA may indeed be a double helix. Later, her images confirming  the helical structure of DNA were shown to Watson without her knowledge. Her work was eventually published in Nature, but not until after two papers by Watson and Crick had already appeared in which the duo only hinted at her contribution. 

2. Even worse than that, the Nobel Prize Committee couldn't even consider her for the prize that they awarded in 1962 because of how dead she was.  The really tragic thing is that it's totally possible that her scientific work may have led to her early death of ovarian cancer at the age of 37. At the time, the x-ray diffraction technology that she was using to photograph DNA required dangerous amounts of radiation exposure, and Franklin rarely took precautions to protect herself. Nobel prizes cannot be awarded posthumously. Many believe she would have shared Watson and Crick's medal if she had been alive to receive it. 

Now that we know the basics of DNA's structure, we need to understand how it copies itself, because cells are constantly dividing, and that requires a complete copy of all that DNA information. It turns out that our cells are EXTREMELY good at this - our cells can create the equivalent of 10, 000 copies of this book in just a few hours. That, my friends, is called replication.

(9:09) Every cell in your body has a copy of the same DNA. It started from an original copy and it will copy itself trillions of times over the course of a lifetime, each time using half of the original DNA strand as a template to build a new molecule. 
 


So, how is a teenage boy like the enzyme helicase? They both want to unzip your genes. Helicase is marvellous, unwinding the double helix at breakneck speeds, slicing open those loose hydrogen bonds between the base pairs. 


The point where the splitting starts is known as the replication fork, it has a top strand, called the leading strand, or the good guy strand as I call it, and another bottom strand called the lagging strand, which I like to call the scumbag strand, because it is a pain in the butt to deal with. 

These unwound sections can now be used as templates to create two complementary DNA strands. But remember the two strands go in opposite directions, in terms of their chemical structure. Which means making a new DNA strand for the leading strand is going to be much, much easier than for the lagging strand. 


For the leading, good guy, strand an enzyme called DNA polymerase just adds matching nucleotides onto the main stem all the way down the molecule. But before it can do that it needs a section of nucleotides that fill in the section that's just been unzipped. 


I guess to start at the very beginning of the DNA molecule, DNA polymerase needs a bit of a primer, just a little thing for it to hook on to so that it can start building the new DNA chain. And for that little primer, we can thank the enzyme RNA primase. The leading strand only needs this RNA primer once at the very beginning. Then DNA polymerase is all, 'I got this!' and it just follows the unzipping, adding new nucleotides to the chain continuously all the way down the molecule. 


Copying the lagging, or scumbag strand, is well, he's a freaking scumbag. This is because DNA polymerase can only copy strands in the 5'-3' direction and the lagging strand is 3'-5'. So DNA polymerase can only add new nucleotides to the free, 3' end of a primer. So maybe the real scumbag here is the DNA polymerase. 


Since the lagging strand runs in the opposite direction, it has to copied in a series of segments and here that awesome little enzyme RNA primase does its thing again, laying down an occasional short little RNA primer that gives the DNA polymerase a starting point to then work backwards along the strand. This is done in a ton of individual segments, each 1,000  to 2,000 base pairs long and each starting with an RNA primer, that we called Okazaki fragments after the couple of married scientists who discovered this step of the process in the 1960s. And thank goodness they were married so we can just call them Okazaki fragments instead of Okazaki-someone's-someone fragments. These allow the strands to be synthesized in short bursts. 


And then, another kind of DNA polymerase has to go back over and replace all those RNA primers. And THEN all of the little fragments get joined up by a final enzyme called DNA ligase. And that is why I say that the lagging strand is such a scumbag!

(12:00) DNA replication gets it wrong about one in every 10 billion nucleotides. But don't think your body doesn't have an app for that! It turns out It turns out that DNA polymerases can also proofread, in a sense removing nucleotides from the ends of a strand whenever they discover a mismatched base. Because the last thing we want is an A when it would have been a G! Considering how tightly packed DNA is into each one of our cells, it's honestly amazing that more mistakes don't happen. Remember, we're taking about millions of miles worth of this stuff inside us. And this, my friends, is why scientists are not exaggerating when they call DNA the most celebrated molecule of all time. 


So, you might as well look this episode over a couple of times and appreciate it for yourself. And in the mean time, gear up for next week, when we're going to talk about how those six feet of kick-ass actually makes you, you. 

Thank you to all the people here at Crash Course who helped make this episode awesome. You can click on any of these things to go back to that section of the video. If you have any questions, please, of course, ask them in the comments or on Facebook or Twitter. 

 

Sex and not dying. That's what Biology is all about. And while the sex part is, I'll grant you, a little bit sexier, not dying is also really fantastic, something that I personally like to do every single day.

I, personally, like to not die in all sorts of ways. Like, I don't jump out of planes, I don't go into active combat zones, I don't do heroin, but I can, however,  spend time wallowing in the filth with my cute bacon-producing friends here and not have to worry about dying. Because, somehow, my body can handle a lot of little devils on my hands, in my hair, in my food, little things that literally want to kill me. There are more potential human killers in this pig pen than there are in all of the world's prisons, but I don't have to worry about it because of the elite team of microscopic assassins that live inside my body. 

My immune system. Ah! That was really close to my hand.

(Intro)

You've heard of some of these little ninjas, others maybe not, but everyone knows the work they do by the trail of dead that they leave behind. Pus, being the most disgusting example. And the work these guys do is pretty hardcore. They not only identify incoming enemies, they eliminate them, and then they keep files on them, in case their kind ever come back. So I don't want to freak you out, but you, and I, are covered in pathogens right now. And you really can't blame them for wanting to get a piece of your action. Your warm, high-energy, nutrient rich, salty, watery action. Your body is a theme park for these guys and although the majority of organisms living inside you actually make your life a little more comfy there are some less helpful viruses and organisms, from here on out referred to as pathogens, that will want to turn your body into a factory for their children. So let's avoid that!

We have two basic ways of doing it. Innate or non-specific immunity that responds to all kinds of pathogens the same way and very quickly whether your body has seen that pathogen before or not. And your acquired, or adaptive immunity, which develops more slowly and requires your body to learn the wily ways of the pathogen before it defeats it.

Every animal has an innate immune system -even sponges- but only vertebrates have the acquired kind. You were born with your innate immune system and from the second that you wiggled away out of the sterile environment of your mom, and into this germ-y, disgusting world, that system has been protecting you.

The thing about the innate immune system is that it doesn't care what it's killing. It doesn't worry about whether it's offing a virus or a bacteria or a fungus, its job is to keep the enemy from getting in, or once it's in, to sneak up behind it and break its neck ninja-style.

The first line of defense in keeping sketchy characters out are the skin and mucous membranes. The skin has so many excellent functions -like keeping your organs in- that it's easy to forget that its primary purpose is to keep things out! It's oily, and kind of acidic, and really not easy to penetrate, and I'm about to rock your world with this, but your digestive tract is also technically the outside of you.

Remember how our bodies are basically just built around a tube right? Well, the inside of that tube is exposed to as much weird grody stuff as the outside of the tube so, your body treats the digestive tract like the front lines of this war which is one of the reasons why your stomach takes no prisoners with the whole stomach acid situation.

In addition to the things like skin we've also got mucous membranes providing another barrier to microbes trying to sneak in. Mucous membranes line all of your internal surfaces that are exposed to the outside like your lungs, and the inside of your nose as well as some other parts of your body like the inside of your mouth, and your eyelids, and your sex organs... Mucous membranes, unsurprisingly produce mucus which is a viscous fluid -you probably heard of it- and it traps microbes and helps sweep them away. This is why illness is so often associated with such awe inspiring amount of goop.

You second line of defense is your inflammatory response.
The honchos here are specialized cells in your connective tissue called mast cells that constantly search for suspicious objects, usually unknown proteins, and then release signalling molecules like histamine when they find them.

Histamine makes your blood vessels more permeable, which allows a whole bunch of fluid to flow to the affected area and that is what causes inflammation. But it also brings in a crap ton of white blood cells -infection fighters- to go all Balrog on whatever's trying to make it's way in. This is great if you get a splinter in your toe or a bunch of viruses in your face, but sometimes something gets into you that's not actually dangerous like pollen or dust or like a peanut and your immune system triggers an inflammatory response anyway even though it's not a big deal. 

This is what we call an allergic reaction and you know what those are like with the swelling and the redness and the mucus production and the itching and occasionally a little bit of death. So that is why we take antihistamines to suppress the histamine trigger so our immune system stop freaking out about nothing. Also, that is why you should always tell people when there are peanuts in your cookies!

Most of the immune system activity that happens inside your body's fortress is done by white blood cells, or leukocytes. Leukocytes are awesome for a lot of reasons but one reason is they've got full VIP access to anywhere in the body that they want to go, with the exception of the Central Nervous System -the brain and the spinal cord- which are, for obvious reasons, super high security areas.

Leukocytes can move through the circulatory system and when they get to a place where they're needed, they can basically send a signal to ask the capillary to open a gap between it's cells, and then it oozes through that gap to the site of the infection. This is called - get ready for it- diapedesis from the Greek for "oozing through". Now there are lots of different kinds of leukocytes, like different branches of your own personal microscopic army. The kind specific to the innate immune system are phagocytes, more Greek this time, "phago" meaning eating, they're just any cells that ingest microorganisms through the process of phagocytosis.

Phagocytes are pretty cool. They can literally chase down invading cells, grab them and then completely engulf them. And some like the super abundant neutrophils, move around the blood stream and can quickly get to where the action is. Once a neutrophil kills an invading microbe, they basically just roll over and die. Dead neutrophils collect together into what we lovingly call pus.

Now the biggest and baddest of the phagocytes are the macrophages the "big eaters" which don't generally travel a lot but instead hang out like body guards in your various organs. Not only do they kill outside invaders they can also detect when one of your cells has gone rogue, like a cancer cell and kill those too. And they unlike the neutrophils don't die once they've killed a bacterium, they can eat up to hundred before they die. Big eater!

Of all the grizzly stuff that goes on in the never ending street war that is your immune system, some of the most gruesome stuff is done by a kind of cell call Natural Killer cells. Which reminds me, I think it's time for our very first open letter!

An open letter, to 1973:

Dear 1973, You had a lot going on: the Vietnam war ending, Roe v. Wade, Watergate... It was a tumultuous time. But part of me wishes that you, 1973, had an opportunity to name everything in biology, because you got one chance to name a new type of immune cell, and you named it "the natural killer cell", and I freaking love that.

I look around at today's script, with all of it's dendritic cells, and macrophages, diapededisises and I think what if we let 1973 name all these things? Would we have "Spiky Death Cells" and "Devourers" and "Oozing action" instead? I don't know. Maybe you would have screwed it up, but I don't think we could have done any worse than all this GD Greek we have to deal with all the time!

Thanks for the Endangered Species Act!

Hank.

OK! Natural killer cells: more than just a great name; also the only phagocyte in the innate immune system that destroys other human cells. When your cells are healthy, they have a special protein on their surface called MHC1 (MHC for Major Histocompatibility Complex), but when your cells are infected with a virus, or when they're cancerous, they stop producing that protein.

So the natural killers are always going around checking up on each of your cells, and when it finds one that's not normal, it pulls out its AK-47 and unloads.

Actually, it just binds with it, and it secretes an enzyme that dissolves its membrane... But still. Killing.

Finally, dendritic cells are a type of phagocyte that hangs out on the surface of much of your body that comes in contact with the environment. In you nose, on your skin, in your stomach, in intestines. They eat up pathogens and then, carry information about them back to the spleen or the lymph nodes where it passes intelligence about what is going on on the war front: the acquired immune system. 

I actually studied dendritic cells in my undergraduate thesis and I kind of fell in love with them. They're lethal, but they're also intelligent. Great heroes from any Robert Ludlum novel. To be fair though, macrophages can do this too.

The activity of these cells give us a chance to transfer from innate immune system to the acquired immune system which is going to make things a little more complicated.

The acquired system has to learn as much as it can about every pathogen it interacts with, store that information and then use it to invent defenses against them. It's your super elite, double secret strike force delta. 

You get to work building your acquired immune system immediately after you're born. Harvesting bacteria and other stuff not just good bacteria -that can help your guts out- but also harmful ones that your body learns from, and stores information about. 

That system keeps an eye out for any foreign substance like toxin or virus or bacteria, even parts of those things that could be tell-tale signs of a bad guy. We call those signs antigens, a word that comes from antibody generator. An antigen is anything that causes your immune system to ID a pathogen and then create an antibody against it.

Now antibodies aren't cells. They're highly specialized proteins produced by B-cells to recognize and help lay the smack down on intruders. But antibodies can't kill invaders themselves, they're just well, proteins after all.

The best that they can do by themselves is sort of just swarm all over the invader, making it harder for it to move and to excrete toxin or otherwise infiltrate other healthy cells. But more often, antibodies serve as tags, attaching themselves to the scumbags and then releasing chemical signals to nearby phagocytes, alerting them that it's dinner time.

Your acquired immune system also has it's own type of white blood cells -not phagocytes, which goes after everything which looks a little bit sketchy- but lymphocytes which goes after specific things that they already know about. There are two major types of lymphocytes, the T cells which from in you bone marrow and them migrate to mature in the thymus gland right behind your breast bone, and the B cells which originate and mature in the bone marrow. What T and B actually stand for is a long story, but if it helps you to remember, T is mature in the thymus, B is in the bone marrow.

We have two different types of lymphocytes because our bodies have two different types of acquired immunity. The cell-mediated response, which is for when the cells are already infected and the humoral response, for when the infection is just in the humorous (the bodies fluid, not in the cells).

First lets look at the cell mediated response, this process mainly involves T cells and there are quite a number of different types of them. 

Helper T cells have a cute sounding name, but in a lot of ways they call the shots for the whole immune system. While they can't kill pathogens themselves, they activate and direct the cells that can. If 1973 had named them they might have been called admiral T cells or something more awesome!

Helper T cells get their information from other immune cells that are out cracking skulls. Say for instance a macrophage finds a pathogen and destroys it, after the deed has been done, it has the ability to shred up the proteins from an invader and put a bit of that antigen on it's membrane surface. 

This is called antigen-presentation because the cell is presenting antigens! A helper T cell can detects when this happens and it comes over to attach itself to the presented antigen. The two cells talk to each other chemically, the antigen presenting cell produces a chemical called Interleukin 1 which basically tells the helper T cell "uh..boss I uh- I found this guy over here and then I broke his neck and then he stuck his guts all over my cell membrane". The helper T cell gives it a look and then releases a chemical called Interleukin 2 which is like a bullhorn. An alarm that tells all the lymphocytes in the area, "There are problems here! We got a problem over here in Sector 69!".

This alarm activates a couple different things all at once. First, the helper T cells starts making copies, tons of copies of itself. Most of those copies differentiate into effector T cells which travels around secrete signalling protein that stimulate other nearby lymphocytes to take action. Most of the rest of them become memory T cells, they're the ones that keep a record of the intruder and provide us future immunity against it.

And now for the saddest story of the day, what happens when the cell gets infected, so infected that it knows that it's a goner that it in fact is being converted from a healthy useful part of the body to an evil zombie farm, pumping out viruses or bacteria, suddenly co-opted to help destroy everything it loves?

Well, with its last bit of strength it'll start presenting antigens, not asking to be rescued but instead asking for a mercy killing. Cytotoxic T cell has the job of granting that request. Once a cytotoxic T cell gets the message from the helper T cells that there is an infection to deal with it starts patrolling the area for any normal cells presenting antigens. When it finds one, it latches on to it and releases enzymes that create holes in the cell's membrane, and eventually breaks down the whole cell, killing the cell and the pathogen in the process. A human cell, killing another human cell.

And now, for the humoral response. The humoral response is designed to catch pathogens that are floating around your body that haven't actually invaded any of your cells yet. The primary players are B cells which are constantly patrolling your blood stream like cops walking the beat until they get a signal from the helper t cell that something is wrong.

B cells are covered in antibodies that can detect and bind to a specific antigen. A single B cell can be covered in a forest of up to 100, 000 antibodies, say for the virus that causes the common cold. And the B cell next to it will have just as many receptors for a different antigen. for chicken pox or something. When a B cell bumps into a pathogen that it recognizes, it attaches to it and starts cloning it self like crazy. Suddenly there are tons of that B cell with the same receptor, but during the cloning process, the clones differentiate into new versions of the original just like the T cells did.

Most turn into plasma or effector cells which use the antibody as a blueprint to create a crap ton of antibodies for that specific pathogen, like 200 antibodies per second. Once, these antibodies are released, they bind to the pathogens like crazy marking them for death until the phagocyte can come along and do the dirty work.

The rest of the cloned B cells mostly become memory cells which have the same receptor, and stick around providing future immunity from this invader.

And we are now very out of time! But I really love this stuff so I didn't want to gloss over anything. Mucus, natural killer cells, macrophages, killing things, breaking them up and sticking them on their cell membranes, effector cells spewing out antibodies and memory cells making sure that our immune system hold that grudge. All because my favorite thing to do every single day is not die.

If you wanna review anything we discussed in this episode there's a table of contents over there, if you have any questions for us we'll be down the comments or on Facebook or Twitter, and we'll see you next time.

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