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, 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 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. 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.