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Some of the most cutting-edge medications are also the most complicated.
They’re called biologics, and most of them are made... by hamsters.
Well, hamster cells.
These complex molecules are used for cutting-edge treatments
for cancer, autoimmune diseases, and more.
And they’re so heavy-duty that we can’t just put them together in a test tube.
We need living cells to make them for us.
So about two-thirds of biologics are made specifically
in Chinese Hamster Ovary cells, or CHO cells.
And while you’re writing that down for your next trivia night,
I’ll tell you it’s for a good reason!
Those little hamsters are biochemical geniuses. I mean, not literally —
but their cells are so handy, biology wouldn’t be the same without them.
Biologics can be pretty much any therapeutic treatment made by living things.
But we often use the term to refer to drugs that are made from proteins.
They can be replacements for the proteins our bodies would normally make, or sticky
antibodies designed to seek and latch onto a specific target, among other things.
And while making a protein is tough for us to do in the lab
because they’re so complex, living things have been doing it for billions of years.
So we can design these drugs to do amazing things…
but we usually ask living cells to make them for us.
To understand how one hamster’s ovaries came to fill this particular role,
we need to go all the way back to the year 1919.
Many people were dying of pandemic influenza,
and it was pneumonia that often dealt the final blow.
But pneumonia-causing bacteria can come in a few varieties, and to treat it,
a doctor needs to know what type their patient is infected with.
At the time, one way to identify the bacteria involved
using the patient’s sputum to infect a bunch of mice.
In China, a researcher named E.T. Hsieh wanted to follow that protocol
to help his patients, but there was actually a shortage of mice.
Chinese striped-back hamsters, on the other hand, were really common.
According to one account, Hsieh was walking down the street in Beijing
and noticed some kids selling captured hamsters as pets.
So of course, he decided to give them a try
as a substitute for lab mice. And it worked!
Hamsters have a lot going for them as lab animals:
they’re small, they’re easy to care for, and they usually don’t get sick
unless a researcher purposely infects them with something.
So, in the 20 years after Hsieh’s pneumonia research,
scientists used Chinese hamsters to study all sorts of disease-causing organisms,
from viruses to bacteria to parasites.
The only catch is that the hamsters were so aggressive, that they needed to be
housed in separate cages or else they would literally kill each other.
So, for decades, scientists couldn’t breed them in the lab.
Instead, labs paid farmers to catch hamsters for them.
The little guys were a common crop pest,
and scientists used them by the thousands.
Eventually, the hamsters were transported to the US, where researchers worked out
how to get them to breed without immediately killing each other,
which made them viable as a lab animal outside of China.
Then, in 1951, researchers discovered something else about these animals:
the hamsters only have 22 chromosomes.
Now, that’s a weirdly small number of chromosomes for a mammal.
Humans have 46; rats have 42, and mice have 40.
But, this was still the dawn of genetics, when figuring out
what chromosomes do was an active pursuit.
Thanks to experiments in the 1940s, the scientific community knew that
chromosomes carried heritable traits from parents to offspring.
A small number of chromosomes made Chinese hamsters
a promising model for studying them further.
Biologists do that by studying mutations.
Like, what happens when the animal has an extra chromosome?
Or when just a chunk of the chromosome has been copied,
or moved from one chromosome to another?
Researchers can isolate and examine chromosomes under a microscope,
where these kinds of changes are often visible.
And a small number of chromosomes makes everything easier to spot.
Now, you can’t look at chromosome mutations by looking at a whole hamster —
or at least, it’s not terribly efficient. And this is where cells come in.
See, this was also a time when scientists were just learning how to
consistently get mammalian cells to grow outside of the organism.
In the late 1950s, scientists at the University of Colorado
got a hold of one of these hamsters and turned several of its cells into cell lines.
A cell line is a single type of cell that’s been made to grow and copy itself
indefinitely in a dish or a test tube.
One of the cell lines that grew well just happened to come from
the hamster’s ovaries — and those became CHO cells.
CHO cells found a place not just in the study of chromosome structure,
but also in toxicology, immunology, and cell physiology.
They were used in discoveries like how cells receive external messages,
how they keep their shape, and how they can stick to each other or move around.
By the 1970s, researchers realized that they could not only study how cells work,
but change how they work with new DNA editing tools.
Thus began the era of biomedical engineering for pharmaceuticals.
So, some diseases are caused because the patient’s body lacks a particular protein.
The idea with biologics is that if you can make that protein and give it to the patient,
that could help treat their disease.
Type 1 Diabetes is a fantastic example. It’s caused by a shortage
of the protein insulin. So it can be treated by administering insulin to the patient.
That insulin used to be pig insulin.
Then, scientists realized that they could take the human gene for insulin,
put it in E. coli bacteria, and the bacteria would read that gene
and start making insulin protein for them.
And behold: E. coli-grown insulin hit the market in 1982.
Now, insulin is a relatively simple biologic drug —
it’s a protein with just two subunits, or pieces.
But insulin is far from the only protein we’d like to be able to make.
Just one of the simplest.
Antibodies, for example, have fantastic potential as medicine.
Normally, they’re parts of our immune systems that attach to specific targets.
They latch on to disease-related molecules
and flag them for destruction by the patient’s immune system.
And we can tailor them to attach to anything we like —
which can be very useful in interfering with the progression of certain diseases.
But antibodies are more complex than insulin. They have four subunits.
E. coli can’t handle such a large project. The genetic code that translates to protein
is the same from bacteria to humans, but the way we process proteins is different.
So to make more complex proteins,
bioengineers turned to one of the best-studied animal cell lines: CHO cells.
But that’s still more challenging than it sounds, because it’s harder to convince
animal cells like CHO cells to pick up new DNA, compared to bacterial cells.
Bacteria are prokaryotes — they just have one membrane to hold in their insides,
with maybe a cell wall to make things stronger,
and then all of their proteins and DNA float freely inside.
On the other hand, animals are eukaryotes,
meaning their DNA is contained in a nucleus, separated from the rest of the cell.
To introduce a gene into bacteria, you just have to get the DNA past one membrane.
For animal cells, it has to get past two.
But in the 1980s, researchers figured out how to basically extort CHO cells
into accepting the genes for biologic drugs.
Here’s what you do: You start with a CHO cell line that lacks the gene
to make an important nutrient.
Grow the cells in medium that has that nutrient, so everything’s fine and dandy.
Then, you create a piece of DNA with two genes.
One is for your biologic. The other is to produce that important nutrient.
When you mix that DNA in with the cells, some of the cells will bring the DNA
all the way into their nucleus, but a lot of them won’t.
So here’s the key part: you take that important nutrient out of the growth medium.
Any cells that didn’t suck up that DNA will die, leaving behind cells
that did pick up the nutrient gene… and the one for the biologic.
This was a major breakthrough for drug production. It was a reliable way to get
genes for drugs into CHO cells, which turned them into little self-replicating factories.
And the first drug made using CHO cells, a blood clot thinner,
was released in the late 1980s.
Now, we’ve implied that CHO cells are used for this because they were… just there.
And certainly, it doesn’t have to be hamster ovaries.
Around a third of protein-based drugs are made using other cell lines.
But in a lot of ways, CHO cells have the advantage.
They accumulate mutations relatively slowly compared to other cell lines,
so whatever gene scientists introduce to make a drug
will probably remain intact for a long time.
They’re also rodent ovary cells, so human viruses are unlikely to cause problems
as a source of contamination.
And they can be grown in big vats of liquid, which is actually important.
A lot of cell lines like to grow stuck to a solid surface —
it’s closer to their natural state.
But CHO cells don’t, and it’s way more space-efficient
to be able to grow your cells in 3D culture than stuck to a billion Petri dishes.
Finally, they do a really good job of making the actual proteins we need.
Proteins are made of amino acids, but that’s not all.
Cells add a finishing touch: a sprinkling of sugar.
No, really: they attach groups of sugar molecules in a process called glycosylation.
Every species has a different way of glycosylating their proteins,
and if you try to put a protein with the wrong sugar pattern into your body,
your immune system will recognize it as not human and destroy it.
But good old CHO cells have nearly identical sugar patterns to human cells.
So drugs produced in CHO cells are ready to go, sugars and all.
CHO cells are one of the most important biological systems in medicine.
They’ve been used to make drugs that treat arthritis, psoriasis,
and even play a part in producing chemotherapy to treat cancer.
And it took a lot of work by a lot of people, over the course of a century,
for Chinese hamsters to become the pharmaceutical powerhouse they are today.
There’s also a bit of serendipity here: some kids were selling
some hamsters in the street that just happen to have a low chromosome number
and a human-like sugar pattern on their proteins.
But sometimes, that’s just how science works.
Now, when I learn about all the wild things that come together to build our knowledge
of the world, I just want to dive even deeper into how it all works.
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