Works in Progress Podcast

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

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

and they do amazing things to keep us going.
 

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

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

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

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

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

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

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

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

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

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

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

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

molecules. There are signalling proteins that help 
cells communicate with each other. So insulin,  

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

of view it feels like, yeah.
Right.
 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

one is 33,000 amino acids long. And guess how long 
it takes to translate its mRNA into protein?
 

Ooh... uh... twenty minutes.
I would've guessed less, but the answer  

can be twelve hours, it can take half a day. It's 
used as sort of a spring in human muscles. So  

thanks for all that time, body, because think it's 
also used in hair to make your hair springy.
 

Huh. Well, that means it's going to take a 
really long time for me to build muscle.
 

Yes, I suppose. Yes.
That's unfortunate.
 

Yeah, we can just give up then.
I got one. What's the most  

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

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

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

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

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

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

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

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

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

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

Oh right.
-and that is collagen. That is  

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

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

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

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

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

Yes.
Well, enzymes are a  

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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