July 12, 2019

How a Chinese hamster came to dominate production of biopharmaceuticals

By Conor McKechnie and Dodi Axelson

How a Chinese hamster came to dominate production of biopharmaceuticals

Little did you know, but a single hamster has been a force of innovation and massive biomedical production. Scientists devote entire careers to so called CHO cells from this Chinese hamster’s ovary. Dodi and Conor talk with a couple of those scientists to figure out why this hamster rules the biopharma world.

CONOR : Dodi in the last episode we talked about the separation of proteins, a scientific discovery that resulted in a sixty-year-old product.

DODI : Still lives today!

CONOR : It made me think of another milestone that happened around the same time. It's got to do with a specific Chinese hamster that changed everything!

DODI : Oh was this a pet of yours in eighth grade or what's the story here?

CONOR : It is even more important than my pet, Belina. Maybe you know the story of Henrietta Lacks?

DODI : Yes, I did read that book: she was the lady who went into Johns Hopkins Hospital in Baltimore, she had cancer - this was in the early 50s, and samples of her cervix tissue were taken by scientists while she was there. She didn't know it then but her cells started an important cell line that is still used today in biomedical research. Terrific story!

CONOR : Exactly: famous, well-known, that's her. And that actually leads us into the story of hamster ovary cells and why they matter!

DODI : Welcome to Discovery Matters! I'm Dodi Axelson

CONOR : and I'm Conor McKechnie. [Music]

CONOR : Let's get back to Henrietta Lacks. You read the book, you say; did you see the show, you know that Oprah played Henrietta Lacks' daughter? [Movie snippet] "Now my brother's all upset cuz everybody come around make money off our momma's cells but I don't care nothing about that! What I care about is knowing about my sister and knowing about my mother!

CONOR : The HeLa human cell line that scientists developed from Henrietta Lacks - Hence the, HeLa …

DODI : Got it, HeLa, Henrietta Lacks.

CONOR : … from her cervical cancer tissue in 1951 was cloned four years later by a scientist called Theodor Puck who was working at the University of Colorado Medical Center. It was there in 1957 where he was handed a Chinese hamster...

Nicole Borth : At that time Chinese hamsters were a standard laboratory animal just as mice would be today.

CONOR : That's Nicole Borth.

NB : I'm a professor at the department of biotechnology at BOKU University in Vienna.

CONOR : Nicole told me how from this one Chinese hamster’s ovaries, Dr. Theodore Puck isolated a cell line.

NB : … and since then this cell line has been in culture in most labs that work with animal cells all over the world so it's been very widely spread. it's kind of had its position as one of the easy to cultivate cell lines and then in around 1985 people started to think about producing therapeutic proteins by recombinant technology; that is, that you put the sequence of the gene that you want to produce into a cell line that does not normally produce it.

DODI : So these Chinese hamster ovary cells or CHO cells proved to be quite flexible at learning new instructions. That's better than my kids can do...

NB : That is essentially the main advantage of CHO cells. Another thing came in that nobody knew about at that time and that is that mammalians or mammalian species - each of them have their specific way of adding sugar groups onto proteins. For instance if you produce a human protein in a mouse line, it will have the human sequence but it will have the mouse sugar pattern; so if you injected it into a human the immune system of the patient would recognize it as foreign and kind of destroy it. Which is of course not something that you want to have in a therapeutic protein because you don't want to inject it only to be degraded. You want to inject it so that it can do its job in the patient.

DODI : Wait, hold on a second, I don't mean to interrupt but this is all starting to sound a little scary and this reminds me of that scene in Harry Potter where Hermione adds cat hair accidentally to that Polyjuice potion. Remember that? And she actually started to turn into a cat... [Movie snippet] "Are you okay? Do you remember me telling you that the Polyjuice potion was only for human transformations? It was cat’s hair I plucked off Millicent Bulstrode’s robes... Look at my face … Look at your tail!”

CONOR : Yeah, you know what, I kind of had that thought too and I put this to Nicole, I wondered if she also felt that when people hear about this then maybe their imaginations start running away from them, and they get this kind of crazy picture that you and I both had in our minds... People start, you know, sporting tails or growing furry ears and whether we really need to experiment in this way. But Nicole reassured me that such worries should be reserved for the pages of Harry Potter and science fiction and what-have-you; and in reality this is actually not the case.

NB : Actually what we're trying to do is we're trying to make it as human-like as possible, simply so that the human patient doesn't recognize it as foreign. I mean we have an immune system that's there to get rid of things that don't belong there, right, so if you make something that is different from the way humans make it, and you inject it into a person ... not much will happen except that this protein will disappear quickly because our immune system will destroy it. The sugar pattern of the Chinese hamster is as human as you can get or closer, as similar to human as you can get. This was a mere coincidence actually, it was good luck on the side of science that the cell line that was chosen to generate the first recombinant therapeutic protein actually was one that would produce these proteins just in the way that humans need them and require them.

DODI : So a specific Chinese hamster was used back in the 1950s, early in the biotech revolution, as a cell line to produce proteins and this chance kind of events spurred the dominance of this cell line to be used within biotechnology.

CONOR : Yeah and that was just the beginning. These CHO cells they're just everywhere now, they're completely instrumental in creating new medicines, new therapies.

NB : There is incredible number of antibody therapies out there now that mostly are in the field of cancer therapy. There are some out there that are starting to generate more and more revenues, that are dealing with rheumatic diseases. There's one treatment where essentially patients receive one injection every half-year and essentially are pain free. I mean everybody knows someone in the family who's suffered from that kind of disease and it's usually been a very painful thing to have. And now with this kind of treatment you have a lot of patients who would not respond to any of the traditional medication,(they)can really benefit!"

DODI : And how many people do you suppose know that they have a Chinese hamster to thank for that?

CONOR : Well, not that many I suppose. If we leave Nicole in Vienna and just look out of the window from here where we are recording in Uppsala - buildings, laboratories where the echo of that one Chinese hamster still rings out. Where CHO cells are being grown and reproduced in huge bioreactors.

DODI : How does that work exactly?

Daniel Ivansson : You have kind of a vial of frozen cells and if you want to create a cellular factory of sorts, to produce a new protein you need to take this vial and then you just culture it in glass flasks - to reproduce more cells. Then, in order to get it to produce a therapeutic protein, you need to introduce a DNA molecule that codes for that protein molecule, into the cells. Today you can actually synthesize this. You know the code for this specific protein...

CONOR : This is Daniel Ivansson …

DI: So I'm a senior research engineer working within the bioprocess R&D, out of Uppsala in Sweden.

CONOR : Daniel's day-to-day consists of designing and conducting experiments...

DI: … randomly integrated into the genome of those cells. Then what you have to do since this is a random process, not all cells would introduce the molecules. Those that introduced it will have it in different copies..."

DODI : And if you were to translate this into everyday words all that Daniel is saying here?

CONOR : Basically what Daniel says is it's kind of like the making of sourdough bread; where you have your yeast and you add sugar and you add flour and so on ...

DI : Exactly like yeast! That’s exactly the same. Those are cells as well of course, and so it's similar but they have a little bit more complex needs than yeast.

DODI : Okay, so you mentioned that Daniel works with experiments on an everyday basis so give me an example.

DI: A lot of those things it's actually cut and paste. You try to, you cut up a DNA molecule, you paste in your DNA molecule in that, and you purify that and then you have that molecule and you want to introduce it into your CHO cell. You have your cells and you actually mix it with DNA and you use a high electric field to kind of create a small hole in the cell so that those DNA molecules can enter the cell. So yeah. You have a lot of different machineries and you manipulate liquids and you go from this tiny kind of volumes when you’re working with DNA molecules which is a microliter volume and then if you culture the cells you can go up to hundreds of liters so it's a big span. Today with the technologies we do have, I mean biology is becoming an engineering discipline. We can start to, if not create, at least change and design life, if you will, to do useful things for us. I mean when we do new DNA molecules we're actually changing life, absolutely.

DODI : Okay, all right, so now this is actually starting to sound less like Harry Potter and more like an old Twilight Zone episode!

CONOR : How do you mean?

DODI : Well there was this famous old episode where two astronauts found a tiny race of little people, no bigger than ants and one of them goes mad with power... [Movie snippet] "What do you think I've got here now? A whole race of little people! They’re scared, Fletch, petrified and so they do what they're told! To a God!"

DODI : Because of the discovery, he starts to think of himself like a God.

CONOR : Okay, so I get it: what you're thinking about here is ethics.

DODI : I suppose I'm thinking about how Daniel knows that he's doing the right thing, how he's not gonna go down the same road as Peter Craig from the Twilight Zone and his God complex.

CONOR : Well, in fact Daniel reflected on this when I talked with him:

DI : So what we are doing is kind of pretty well boxed-in. I mean we are trying to design life And, if you will, to be better at producing a therapeutic drug. And we are doing that, as I said, with an isolated cell line that is just growing in the lab. And that those cells will never be released into the environment and so on. So, I mean it's pretty boxed-in but if you think bigger of it, of course it has... if you start talking about applications on humans or animals in the wild, it's a whole different thing.

DODI : So, what's next?

CONOR : Well, for Daniel there are two major things:

DI : … and both comes back to the fact that Today, treatments are being becoming more and more personalized: so you need to develop more different drugs and they need to then be also cost effective because normally therapy biotherapeutics are quite expensive. So how can we develop those drugs quicker and how can we produce them at a lower cost? So then there are two things: one thing is to make CHO cells that are much more efficient at integrating those DNA molecules that are needed to produce the cells; so that means that we want to develop efficient cells where the process is not random when integrating the DNA molecules, but it is targeted so that we know it comes to the same place every time and that same place is highly active before producing the proteins. So that's one thing. The other thing is about the yield and then you would like to kind of change the CHO cell with modern techniques such as you heard about genome editing and CRISPR-CAS9 of those things. You would like to change the genome of the cell so that becomes even more efficient at producing proteins. So that's another big area for CHO cells. Those two things together making it much more efficient at developing cells that produce and those cells should be able to produce at a much higher level.

CONOR : So Daniel is saying that he would have a really large volume of CHO cells but that he would be able to personalize them and that it's possible to have that personalization on a massive scale!

DI :  You want to produce many different protein drugs, more than it has been done in the past. In order to do that, the process of developing those cells that produce those must be much quicker and cheaper. And you would also like it to be cheaper to produce the proteins - and that had several important impacts. I mean the manufacturing environment will be different; it used to be that you have a blockbuster drug that you want to produce in metric tons, for example, and then you have manufacturing facilities that are built for the sole purpose of developing or producing that particular drug: huge tanks that I run in the same way every time. Now what will probably happen is that you need to have flexible manufacturing sites where you produce many different drugs throughout the year. And then comes, in order to make the most of such a Factory, you would like every single molecule you want to produce that it can do that in the shortest possible time. And if you have CHO cells that produce a lot more of that protein, you can run the process in less time and you can switch over to a new product. Producing that product and so on so that you can now get an efficient means of supplying the demand of different personalized medicines to the market.

DODI : So even though medicines in production will be changing, Daniel is saying at the end of it all we'll still have that original Chinese hamster and her ovaries that was handed to Theodore Puck.

DI : Of course, there are attempts to try to see if it could be changed, the cell, to something else. Or do we need a cell at all? Can we take out the most important process from the cell and make that possible? But I definitely think that we will use cells for many, many years to come and CHO cells, since it is so heavily entrenched in the area I think it will be used. And with the technology that is coming today, you can start really changing things. It doesn't really matter what you start with because you can mold it into something different. You could start with a human cell, you can start with something else: the engineering principles will basically be the same and you will create something new. So the CHO cells of the future will not really be CHO cells even though you started out from those CHO cells, they will be something different, a new life-form!

CONOR : That's it for this episode of Discovery Matters. We hope it makes you look differently at hamsters forever more.

DODI : Rate us on your podcast app and share the love by sharing this podcast. Thank you for listening!


Our executive producer is Andrea Kilin. Discovery Matters is produced in collaboration with SoundTelling production and music by Thomas Henley.