July 02, 2019

How the hunt for a new way to make jam changed the way we make medicines

By Conor McKechnie and Dodi Axelson

How the hunt for a new way to make jam changed the way we make medicines

Dodi and Conor discover how jam played a part in paving the way for biopharmaceutical drugs. Sixty years ago, Swedish scientists happened upon a new method of protein separation through chromatography. The very same technique continues to be the foundation for modern biomedical manufacturing.

DODI : Conor you're British and I guess that means that you drink your tea with jam and bread, as the song goes, isn't that right?

CONOR : I do a drink tea with jam and bread and you're a Yank which means you do jam and peanut butter.

DODI : I do with no regrets. I love it. I think it's delicious. But we're talking about jam today because it is a pretty important part of our lives around the world.

CONOR : If you say so.

DODI : Jam is important in a lot of contexts and it's been important in scientific discoveries.

CONOR : And that's going to be what matters in this episode

DODI : …Of Discovery Matters! Brought to you by the Life Sciences Team at GE Healthcare. I'm Dodi Axelson…

CONOR : …And I'm Conor McKechnie. So, jam.

DODI : Yeah, jam. Today we're gonna be telling a story about looking for one thing and finding another. And about the importance of keeping an open mind and how it can lead to game changing consequences. We're going to be talking about a remarkable way to separate proteins and change the way medicines are made. Six decades ago a product called Sephadex was born and it changed everything. It's still out there today stronger than ever using basically the same recipe since its birth.

CONOR : So where exactly does the story start?

DODI : From the very beginning, as they say.  So, to help us tell the story I sat down with Jan-Christer Janson, a Swedish guy who was a professor and is now professor emeritus at Uppsala University

JAN-CHRISTER JANSON : The Sephadex story starts with two Nobel Prize winners. The (Theodor) Svedberg got the Nobel Prize in 1926, and Arne Tiselius got the Nobel Prize in 1948. I would say they laid the foundation to the methodological research that was to be pursued for decades at Uppsala University. But when it comes to Sephadex, a very important circumstance is the Korean War (Corrected for factual accuracy). During the Korean War many Swedish companies turned to Swedish universities for help to develop new products. For example Svedberg was asked to produce synthetic rubber, neoprene. At that time it was necessary for tires- airplane tires, and other tires. Similarly the Swedish sugar company in Arlöv, in Skåne, they turned to Tiselius and asked if he could help them to find some useful substance in beetroot juice, sugar beet root juice.

DODI : Sockerbolaget, or the Swedish Sugar Company had a theory that sugar beets might have pectin in them.

JCJ : Pectin is a polysaccharide that gives a gel for jams, etcetera.

DODI : So in 1941, Arne Tiselius asked one of his students called Bjorn Ingelman to look into whether beet roots contained pectin.

JCJ : But he couldn't find any pectin of any value. But he found another polysaccharide, Dextran.

CONOR : Ah so this is one of those beautiful mistakes that science can serve up like Alexander Fleming and his discovery of penicillin or the angina drug that became Viagra.

DODI : Exactly. And when it comes to the story of Sephadex, these ‘beautiful mistakes’, as you call them, pop up a lot. Back to Dextran

JCJ : Dextran is formed when sugar is attacked by a bacterium called Leuconostoc mesenteroides. During the warm summer time this bacteria, they grow in the beetroot juice, so when they arrive to Uppsala and Ingelman started to work with them, he only found Dextran. He told the sugar company, ‘Sorry I can't find any pectin but I have found Dextran. And then the engineers at the sugar companies said, ‘Ahaa, Dextran!’. What Ingelman did was to contact a friend of his Anders Grönwall, so Ingelman and Anders Grönwall, they started to make the Dextran purified Dextran. And then they injected the Dextran into rabbits. Why? Because in the early 1940s, a professor in Gothenburg called Örjan Ouchterlony had developed immunodiffusion technology. Immunodiffusion means that you can have precipitation lines between antigen and antibody. So, Anders Grönwall and Björn Ingelman realized that if we can't create antibodies to Dextran, then we can easily, using this immunodiffusion technology, which was new at the time, then we can find out which batch contained Dextran and which does not. So, in order to produce antibodies, they injected Dextran into rabbits. They got no antibodies.

DODI : But this setback didn't deter Grönwall and Ingelman. In fact this just spurred them on even more.

JCJ : These two people were clever enough to realize, ‘Aha, you have a substance that can be injected into an animal without raising antibodies. It must be useful for medical purposes!’ So, they contacted a very small company in Stockholm called Pharmacia.

CONOR : Aha, so now I see where the name Sephadex comes from. Separation, Pharmacia, and Dextran.

DODI : Yep that's right.

JCJ : And fortunately the President of Pharmacia was clever enough to realize, ‘Here we have the possibility to get a modern drug. Or this is our opportunity to get into modern medicine.’ So they sign an agreement with Grönwall and Ingelman to start to develop Dextran, and they contacted the sugar company. The sugar company started a daughter company, called Sorgona  to produce Dextran on a huge scale. 1946. Pharmacia had a product on the market. Can you imagine? They had a pharmaceutical product on the market, only five years later. It's amazing.

CONOR : So, in the middle of the Korean War (Corrected for factual accuracy), back in Sweden, Dextran has become a plasma substitute in battlefield medicine and the guys who've discovered its use in this way just kind of stumbled upon it.

DODI : That's right.

CONOR : But that doesn't bring us to Sephadex yet, though.

DODI : Not yet.

CONOR : OK.Right.

DODI : Because Ingelman was still stuck on the idea of finding pectin somewhere, and this is where jam and bread comes in.

JCJ : At the Department of Physical Chemistry, Ingelman kept in his mind the problem of pectin…to create a gel for jams, thickener for jams. Swedish people like lingon-berry jam, as you know, and this is why pectin is very important for the jam industry. So Ingelman had not forgotten that problem. When huge quantities of Dextran came to his disposal, he tried to make gel of Dextran for making jam, and he made some very nice gels and he contacted the sugar company and asked, ‘Here, I can make a gel with Dextran. What do you say? Are you interested?

No, they were not interested. Then, Ingelman was clever enough not to apply a patent, not to publish that he could make a gel from Dextran an epi-chloral hydrating crosslinker, because he was clever enough to realize this must be a product! Sooner or later, this must have an application, medical or whatever. So he kept silent. Fortunately, he kept silent!

But Ingelman became research director and he started to recruit and he recruited Jerker Porath and Per Flodin. So they spent several years in the early 50s to develop this technique of column zone electrophoresis (9:30). And they tried many different packing materials, none of which was very good.

DODI : So Per Flodin joins Pharmacia, and he becomes the head of the Dextran laboratory. But he was stumped and then his boss, and our friend Ingelman, mentioned that he'd actually made crosslinked Dextran years before.

JCJ : So, Flodin realized, ‘Oh. Crosslinked Dextran…totally non-charged. No adsorption effect. Perfect for packing into column zone electrophoresis columns (10.05). So, Flodin started to make crosslinked Dextran and grind it into particles and gave it to Porath for testing for column zone electrophoresis (10.17) and then comes the question: Was there any electricity or not? There was a separation occurring, where small molecules come out after large molecules. This is what Porath found out in a zone electrophoresis column packed with the crosslinked Dextran particles and then Porath said to Flodin that this is exactly the same result as we obtained with the starch gel. Both Flodin and Porath realized that now we have a product.

DODI : So they pitched their product to Pharmacia and they were given the green light through a written memo. So that's the story of how Sephadex came to be. It was the first tool of chromatography used to purify protein and it was the tool that enables scientists to learn more about proteins -- what they look like and how they can be used in bio pharmaceuticals and for treatments.

CONOR : So that's history. What about the state of Sephadex today?

DODI : For that I want you to think about another image. Probably your favorite weekend activity. You know how you load up the washing machine?

LOTTA LJUNGQVIST : You separate socks and trousers in one, and then you separate them by color, and then maybe you separate them by different fabrics? So we have all these tools that separate them for you. And then we also have tools called Affinity Chromatography that would separate your particular favorite blouse with that color, with that design, and, sort of, only that one that will pick it up.

LOTTA LJUNGQVIST : I'm LOTTA LJUNGQVIST . I'm the CEO of GE in the Nordic region. Sephadex has been a part of my life, and also a little bit more modern sibling of Sephadex, the protein-A based resins. I did my pHD at the Royal Institute of Technology on using protein A- molecules for various Affinity Chromatography. That's where I started my scientific journey

DODI : And Lotta told me that, though Sephadex is steeped in history (sixty years’ worth of it), it's not bound to it.

LL : It's not only the ones that started to use this product sixty years ago. People are also using it now for the first time and they're using it in developing new manufacturing processes for new medicines. If you look upon how many drugs are used today, it's several hundreds of these that are based on proteins. They still use the same type of tool box Sephadex and Sephadex’s new siblings ...then that's sort of fascinating to see what impact that tool has made on the global health.

CONOR : So we've seen where Sephadex came from and where it is now. But I can't help wondering if it's got another 60 years in it. What about the future?

HENRIK : My name is Henrik Ihre and I'm the director of something called Custom Consumables. So we're essentially making customized chromatography resins, pre-packed columns, and I've been here for almost 20 years now.

DODI : At this point I was thinking that maybe the future of Sephadex would be one of change, like a new cell phone. There's always something new and better on the way. So maybe the future of Sephadex means a new and improved product?

HENRIK : New and improved could be very good for new processes. Otherwise, you want things to be like they've always been.

CONOR : Okay, so if not new improved then what exactly is the future of Sephadex?

HENRIK : I think the Sephadexes, especially the Sephadexes that people use for existing processes, they will be the same. And I think that's exactly what our customers are asking from us. No changes. So what we need to do now, we need to listen… I think the expression is, we need to ‘put our ears to the rails’ and listen to what our customers are saying to understand what products we need to develop for the next generation.

DODI : Listening. For sure, it is important, and as Jan-Christer tells us, the story of Sephadex is not at all over. In fact, this idea of finding things where you weren't looking for them has attached itself to the story of Sephadex now and its family of products.

JCJ : I am proud of having followed, you know, (sic) the development of the company and the products. It's amazing that Sephadex G -25 is growing! Every year, if you have a good product you can always rely on, if it's well spread over the world, many different brains come in contact with the product. New applications come out all the time! That's the funny thing with the material and I think Sephadex G 25 is a wonderful example of such a product. You know, there is a man - he's dead now - Ulf Rothman in Malmö;. He happened to drop some Sephadex G 25 in a sink and saw that (sucks in breath) it sucked up the water in the bottom of sink and then he realized, ‘Oh my God, that G 25 could probably be used as a wound healer to suck up all the exudates from a wound!’, and a product was created called Debrisan, which is Sephadex G 25.

CONOR : That's all for this week on Discovery Matters. Next time, how a Chinese hamster changed medicine forever.

DODI : Thanks for listening, and rate us on your podcast app. Bye!

Our executive producer is Andrea Kilin. Discovery Matters is produced in collaboration with Soundtelling. Production and music by Thomas H.