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In today's episode, we're going to talk 
about the wonderful world of proteins.
 

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Proteins are all around our body. 
We use them in our daily lives,  

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and they do amazing things to keep us going.
 

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Protein design just won a Nobel Prize 
and we are going to do a mini-series of  

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episodes here to talk about AlphaFold and 
other AI systems used to design proteins,  

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whether people can increasingly design dangerous 
proteins, not just medicines, and whether protein  

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design can help us get cures for some of the 
toughest diseases that still plague humanity.
 

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But first, let's start with the basics. You might 
remember being in high school biology and seeing  

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a simple diagram of a cell. It probably looked a 
bit like a fried egg or a sunny side up. There was  

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the nucleus, which was a bit like the egg yolk. 
And then there were a few other things scattered  

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around, like mitochondria and ribosomes, 
but that was a massive simplification.
 

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In reality, cells are incredibly busy. There 
are billions of molecules in every cell,  

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including loads of proteins, which have different 
functions. So let me just think about what are  

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the different things that the proteins are 
doing? Well, there are structural proteins;  

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they provide shape and strength to cells. 
There are storage proteins; they store  

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little molecules. There are signalling proteins 
that help cells communicate with each other.  

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So insulin, for example, is a hormone, and 
it's made in the pancreas and it tells cells  

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to take up glucose from the bloodstream, 
and that lowers blood sugar after eating.
 

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There are also transport proteins that 
move molecules between cells. Haemoglobin,  

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for example, is a protein in red blood cells 
that binds to oxygen and carries it around in  

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the blood. There are also enzymes — enzymes speed 
up chemical reactions in our body, by lowering  

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the activation energy needed for them. There are 
regulatory proteins that control other proteins  

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and pathways. And there are defence proteins 
that protect us from attack; so antibodies are  

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a type of protein. Snakes and spiders have 
venoms, which are proteins that help them  

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disable their threats. There are so many different 
types of jobs that a protein might have, and many  

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proteins have multiple jobs at the same time.
And this means that this basic diagram view,  

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that you might've had of a cell, was quite 
simple. In reality, the cell is extremely  

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busy. It's more like a bustling city, and there 
are literally billions of molecules, proteins,  

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DNA, RNA, fats, sugars, and ions — all moving 
around, reacting and interacting with each other.
 

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Every part of the cell has its own job and it's 
a bit like different districts in the city.  

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There's a great blog post by Niko McCarty where he 
describes this, and I thought it would be helpful  

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just to have a sense of what's going on. He says, 
"A microbe's guts are a veritable Times Square,  

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crowded with sugars, proteins, and water molecules 
that ricochet and smash into each other billions  

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of times each second. Space is limited. A 
bacterium's insides are 70% water by mass;  

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the other 30% is dominated by proteins first, 
followed by RNA and lipids. DNA accounts for  

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just 1%. And all of this stuff fits inside a 
volume that is one quadrillionth of a litre.
 

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That's a lot of proteins and I 
can't even see one of them.
 

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Right? They're so small. And so if you think 
of this city — of each cell — the nucleus is  

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something like the city hall, it's managing the 
information; it has instructions for what should  

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happen. There are mitochondria; the power stations 
of the cell. There are ribosomes that construct  

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new proteins. And then there are proteins, that 
are the workers and the machines of the city,  

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but they're also the structural components and the 
signalling molecules and all of these things.
 

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Our body is doing so much 
with all of those proteins.  

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Are proteins used outside of the body too?
They are! In fact, if you've done any cooking,  

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you would know, for example, that chemical 
reactions change the proteins that you're cooking  

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with. So, for example, if you cook an egg white, 
it becomes firm when it's cooked. That's because  

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the heat denatures the proteins — it makes them 
unfold — and then it makes them coagulate into a  

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different kind of mesh, and that makes it opaque.
There's also gluten, which is a protein that gives  

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bread its stretchy texture — that's made of two 
proteins. There are also lots of proteins that  

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are used in industry and biotechnology. If you've 
done your laundry recently, you might have used  

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a detergent that was made of enzymes, and the 
enzymes break down stains, like fat or blood.  

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Then there are a bunch of proteins that are used 
in baking and brewing and textile manufacturing.  

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Of course there are lots of proteins that are 
used in medicine as well. So I mentioned that  

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antibodies are a type of protein, and lots of 
medicines are types of antibodies. There's also  

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insulin, which people use in diabetes; it's 
a protein that is also a therapeutic drug.
 

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What actually are proteins? What do 
they look like and how do they form?
 

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Proteins are long chains of amino acids. You 
can sort of think of that as like beads on a  

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string. And then that string, or that chain, is 
folded into some kind of 3D shape. The string  

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is the protein's backbone, and each bead is an 
amino acid. Each amino acid has unique features.  

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So as this string falls into a structure, you 
can kind of imagine that maybe happening at a  

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small scale — maybe there's like a little helix 
of the string in some place, or maybe there are  

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two parallel strings next to each other. But 
imagine that... we have to kind of zoom out  

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and this whole 3D shape of the protein could also 
be connected to another protein; it could be two  

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proteins together, making a protein complex.
How is that made? I know I eat some protein,  

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but I think we make some too.
That's right. So you have lots of  

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DNA in your cells, and the DNA, which is the 
code of life, is the instructions for which  

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proteins to make and how they should look. 
The DNA is transcribed into RNA, which is  

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typically this temporary molecule, and then the 
RNA is then translated into protein by ribosomes.  

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They sort of form one-by-one into this chain, and 
then rapidly fold into a much bigger structure.
 

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This was kind of interesting to me because when 
I was reading this, I was thinking, okay, how did  

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the first protein that was ever discovered look? 
What did people think when they first saw it?  

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And that was fascinating because the first protein 
whose structure was determined was in 1958,  

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and that was myoglobin. This was determined 
by John Kendrew, a British scientist. When he  

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discovered this, it was only four years after 
the discovery of DNA's structure — DNA is of  

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course very beautiful; it has this symmetrical 
structure, of this helix. And he was really  

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disappointed when he figured out what myoglobin 
looked like. He wrote in this paper: "Perhaps the  

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most remarkable features of the molecule are 
its complexity and its lack of symmetry."
 

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Oh no, it's ugly.
But in hindsight, the irregularity is exactly what  

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makes proteins so powerful. It's not really like 
DNA, which has this kind of linear messaging — it  

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has the code, and then the code just linearly 
turns into RNA. But a protein is actually doing  

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multiple things. It's in the cell being bombarded 
sometimes with lots of different molecules,  

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and it needs to be able to recognise these 
different shapes and structures, and sometimes,  

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it has multiple functions — and this function 
of every protein depends on that 3D structure.
 

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The folded shape means that there are like 
little pockets, grooves and surfaces that  

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the protein uses to bind to other molecules, 
or carry out specific chemical reactions,  

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or even receive signals and then change shape in 
response. That means the same protein molecule  

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might be doing multiple things at once. It could 
be doing a chemical reaction, but also binding  

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to something else, and then when it gets some 
regulatory signal, it could be changing shape and  

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stopping that chemical reaction from happening.
So there's benefits to being a weird blob. There's  

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nothing wrong with being a weird blob.
I thought it would be fun if we both share  

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some fun facts about proteins. I found these from 
the book Biology by the Numbers, which is a great  

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textbook, and it's also free online. The authors 
create these rough estimates and pull together key  

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numbers on lots of different things related to 
cell biology. Some of them are rough estimates,  

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but they're kind of our best guess right now.
Hit me.
 

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Alright, first one, how many 
proteins are in a human cell?
 

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They're busy, so I'm going to guess a lot. 
And I'm going to guess it depends on the cell,  

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but I will go with a hundred million.
That is a lot, and it does depend on  

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the cell. But the estimate for the average 
number is ten billion proteins per cell.
 

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Oh no. Two orders of magnitude wrong, not 
a good start. Okay, well, I've got one.  

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Which is bigger: the protein or the 
mRNA that codes for the protein?
 

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Um... surely the protein is bigger, no? Why would 
the instructions be bigger than the protein?
 

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That's what I always think, and it's the other 
way around. So the mRNA is bigger — you look at  

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them side by side - well, images of 'em - and 
the mRNA is like 10 times bigger. Because each  

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amino acid is coded for by three nucleotides, 
and the nucleotides themselves are bigger and  

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heavier. So it's counterintuitive to me, 
but you know, it makes sense, I guess,  

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when you think about it physically.
That does make sense... well,  

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I don't know if that makes sense. I feel 
like I need to think about this more.
 

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Yeah, it doesn't make sense from a computer 
science point of view, but from a physical point  

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of view it feels like, yeah.
Right.
 

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I have one. So, you know, as a small person, 
I wanted to find out which protein was the  

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smallest. Do you have any guesses?
The protein that's the smallest? Well,  

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the definition of a protein... I wonder if I'm 
allowed to have- it's got to have at least two  

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amino acids, so I know it's not going to be 
less than two, but that probably wouldn't  

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count as a protein because it wouldn't fold 
into anything, wouldn't have much function.  

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So I'm going to guess philosophically, 
two, and then, literally, more than two.
 

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Well, you're right. I think the typical definition 
of a protein is something that floats on its own  

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in water and can fold into a stable shape. If 
you use that definition, then the smallest ones  

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are some 20 to 30 amino acids long. There are 
actually lots of really tiny proteins, and these  

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tiny proteins are called "micro proteins", and 
they're less than a hundred amino acids or so. One  

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example that's actually even smaller than 20 or 30 
is somatostatin, which is a hormone that controls  

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other hormones — so it controls growth hormone and 
insulin. — and that's only 14 amino acids long.
 

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Oh wow, it's that small. Oh okay.
Right. It still has a stable shape,  

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because parts of the chain are connected to each 
other. So it's not considered a typical protein,  

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but it's a Itpeptide and it's very small.
Got it, okay. What's the biggest? I think you  

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know the answer to this one.
I think I do. Is it titin?
 

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It's titin. That's the biggest human protein at 
least, I don't know outside of humans. But that  

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one is 33,000 amino acids long.
I got one. What's the most  

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abundant protein on earth?
I am going to guess it has something  

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to do with photosynthesis, because that seems 
like one of the biggest functions on earth.
 

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Very good guess. So it's kind of a tie, and 
we're not really sure which one is more abundant,  

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so that was a bit of a trick question.
Oh wow.
 

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But one of them is RuBisCO, and that is used in 
photosynthesis; it's used to grab carbon from the  

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air and turn it into useful organic material. And 
that's used by all photosynthetic organisms. And  

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scientists estimate that there are about five 
kilogrammes of RuBisCO per person on earth.
 

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Oh my god. What?! Wow.
I guess there are a lot of plants.
 

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Yeah, fair enough. They're winning. 
They're winning... for now...
 

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There's actually the second, which 
might be ahead. We're not sure-
 

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Oh right.
-and that is collagen. That is  

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used as a kind of structural protein, and it makes 
up about 30% of the protein mass in your body — so  

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about three kilogrammes of collagen per person. 
But it's not just humans that have collagen,  

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it's also the livestock and all animals. That 
means there's- well, the total number- the total  

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mass of livestock is also enormous, right? And so 
this means there's roughly four to six kilogrammes  

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of collagen per person on earth.
Ready for another fun fact?
 

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Yes.
Well, enzymes are a  

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type of protein that speed up reactions... so how 
much do you think enzymes speed up reactions?
 

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Mmm... a thousand times, maybe? Two thousand? 
I feel like... a lot. But I don't know.
 

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A lot. A lot. And I bet some do a thousand, but 
if you're really looking at the best of the best,  

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we're talking billions of times, and possibly 
trillions of times, so we're talking millions  

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of reactions per second per enzyme in some 
cases, and just totally changing what is  

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happening at the molecular level.
That's crazy. That means, I guess,  

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some reactions just wouldn't happen 
if the enzymes weren't there.
 

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Oh, absolutely. Yeah. I mean, 
statistically speaking, yeah.
 

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So we were talking about protein folding 
the other day, and I was thinking: well,  

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how fast do proteins fold into 
shape? Do you have any guesses?
 

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Oh... that is a tough one because, well, we just 
had a very long protein that took forever, but  

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I bet most proteins don't take long at all. The 
folding has to happen quickly, otherwise they'll  

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get distracted by other forces. So I will go with 
tenths of seconds, no, hundredths of seconds.
 

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Pretty close. So, on average, 
proteins fold in milliseconds,  

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but some proteins fold really quickly, in micro 
seconds, which are a millionth of a second. And  

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I guess you're right that it really does have 
to happen fast, because there's so much other  

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stuff going on in the cell. It could just be 
bombarded with something else before it folds.
 

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Yeah, well, no fun. One final one 
from me. How quick do they move? Let's  

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say you're in a cell. How quick does 
the protein move across the cell?
 

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I love the idea that I've shrunk myself to the 
size that I can fit inside a cell. And now I'm  

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trying to race with these little proteins. 
To get across a cell... uh... I dunno. A  

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second? Maybe half a second? I dunno.
A small protein could be 10 milliseconds  

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to get across a cell. The thing, though, is that 
cells are small. So if you haven't shrunk yourself  

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all the way down, and are just visualising 
the human scale, how long would it take a  

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protein to move a whole centimetre? Well, then 
you'd need 20 days for some of the proteins.
 

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Well, so at first I thought you said - 
okay, that's quite fast - they're taking  

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10 milliseconds to cross the cell. But 20 
days to travel one centimetre is quite slow,  

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I could do that much faster.
Yeah, I think you're going to win.
 

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... but maybe not if I'm shrink to that size. 
Okay, I got another one. How fast are enzymes  

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colliding with other molecules in the cell? Or 
how many collisions are there per second?
 

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Okay. I have the sense that things are 
just crazy up in there and everyone's  

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sort of bumping around. So I'm going to 
say a thousand collisions a second.
 

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Well, you were right with the idea.
Oh no, I should have just said "A lot."
 

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But I think the estimate is 500,000 molecules 
are colliding with an enzyme per second.
 

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Wow.
And that's a lot! And that makes me think that  

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proteins have to be really specific in how they 
bind to their targets. It's like, you know, if  

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you're at a really crowded party and you're trying 
to find a friend, you would just bump into so many  

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people before you actually find your friend. So 
you have to actually be able to recognise them  

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among the 500,000 random strangers around you.
Yep. That's tricky. Okay, Saloni,  

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what's your favourite protein?
My favourite protein is tubulin. It's part  

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of microtubules. The microtubules are kinda the 
skeletons of your cells... That sounds a bit grim,  

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actually. But they are basically formed of these 
hollow tubes that are made of this protein,  

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and each of the little structures is kind of 
like a tiny corn kernel. That tube can sort of  

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assemble and disassemble in response to signals, 
and that means that the entire skeleton can kind  

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of assemble and disassemble... which means the 
whole cell can change its shape or its size and  

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move around, because of these microtubules. 
The microtubules also act as tracks to move  

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things around, so they're a bit like a cellular 
railway or something, which I think is just super  

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cool. And I remember learning about this in 
my undergrad and just seeing some diagrams  

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and thinking, wow, that's amazing.
That's a good one. I haven't even  

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better one though, which is gluten 
in bread! Woo! I'm a bread guy.
 

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That's a good one.
We each have our favourites.
 

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This was the first of a series of mini episodes 
we're doing on proteins. Stay tuned for our next  

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episode on the history of Insulin. And if you like 
this, share it with your friends and subscribe.