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to see how you can take your STEM skills to the next level. [♪ INTRO] 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. And this is where Brilliant can help. They
have tons of courses and daily challenges, all designed to help you turbocharge
your math and science thinking skills and make sense of this wonderful, weird world. Like their course Knowledge and Uncertainty, which helps us put numbers
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but we can learn how to account for it. If you’re feeling ultra-curious, you can
get 20% off an annual Premium subscription, with access to all 60+ courses,
at brilliant.org/scishow. [♪ OUTRO]
Very interesting! I read that Enbrel was made with hamster ovary cells, but I didn’t get a full explanation of how it works. I wasn’t able to find an explanation. Thanks for sharing!
That’s really cool. Hamsters Savin lives
I love Sci-show. Thanks, hamsters for my medicine!