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  • Thanks to Brilliant for supporting  this episode of SciShow.

  • Go to Brilliant.org/SciShow  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 aslab 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 efficientAnd 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 toxicologyimmunology, 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 projectThe 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 prokaryotesthey 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 nucleusseparated 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 cellssome of the cells will bring the DNA

  • all the way into their nucleusbut 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  geneand 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 werejust 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  on the things we don't know.

  • We can never eliminate uncertaintybut 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+ coursesat brilliant.org/scishow.

  • [♪ OUTRO]

Thanks to Brilliant for supporting  this episode of SciShow.

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