Hard Drugs

Saloni Dattani:
I hope you're excited for this episode because we're going to talk about the history of insulin in 15 minutes. That sounds tough considering our first episode about the history of HIV treatment was almost five hours. But I am confident that we can get through this.

Jacob Trefethen:
We can do it together.

Saloni Dattani:
We can do it. We'll start in the 1920s, and at this point, scientists were trying to develop treatments for diabetes and they were trying to study the pancreas. They knew the pancreas was involved and it seemed to produce something that was reducing sugar levels.

The pancreas is a small organ behind your stomach, and they knew it was involved because if you destroyed parts of the pancreas in animals, they would have problems controlling their blood sugar. They developed symptoms that were diabetic, so they would have frequent urination and they would produce sweet urine and soon they'd die.

There was a possibility that something in the pancreas was protecting people regularly from diabetes and diabetic symptoms. And in the 1920s, scientists at the University of Toronto figured out how to extract cells from the pancreases of animals, and injected insulin from these cells into a 14-year-old boy with diabetes. In 1922, he was essentially on his deathbed, and he was the first person in history to receive an injection of insulin.

Jacob Trefethen:
Whoa. A hundred years ago.

Saloni Dattani:
A hundred years ago, and his symptoms improved dramatically. And this was a breakthrough. I thought it was just so interesting to think of how much has happened in that a hundred years, and they received many requests to basically share this insulin, and the process they had developed. There were two companies that scaled that up. In the US, there was Eli Lilly, and in Europe, there were two Danish researchers who brought this treatment to Europe and developed the company that became Novo Nordisk and produced insulin as well.

But at that time, it was still a very inefficient process: they had to extract insulin from dead animals, like pigs and cows, and within the pancreas, only around 1% of cells produce insulin at all, so it's extremely inefficient. This means that you would require a lot of pancreases from dead animals to produce any insulin. Even in the 1970s, it took 8,000 pounds of pancreas glands from 23,500 animals just to make one pound of insulin.

Jacob Trefethen:
No, that's horrible.

Saloni Dattani:
It's horrible. And it's a lot, right? And it was still a breakthrough. Before that time, one common treatment for diabetes was a "starvation diet". There was another diet where just people had to just stop eating entire food categories because they would have a spike in sugar levels in their blood, and that could eventually lead to coma and death. Gradually, over time, just slowly, this process became more efficient; people figured out slightly better ways of doing it. But it was still limited by the amount of animal that was supplied by the meat industry. As diabetes patients were treated, more of them survived for longer, and the demand for insulin grew, and people worried that it would be really hard to meet all of that demand with a process that required extracting it from animals.

Another problem was even in the 1940s, '50s and '60s even, people with diabetes would have to dose themselves at home. So they would have to inject themselves with a thick needle that they would sharpen themselves with a razor stone. And they had to boil the glass syringes that they used to inject themselves and then reuse those syringes. This was surprising to me as well. I didn't realise this, but disposable needles didn't become common until decades later. So it was both painful and difficult and could lead to contamination.

Jacob Trefethen:
This reminds me of some horrible scenes in the film "Killers of the Fire Moon", which-

Saloni Dattani:
I haven't seen it!

Jacob Trefethen:
-thankfully I don't have time to get into. Well, you're going to have to watch it after because I can't spoil it for our audience.

Saloni Dattani:
What's the- oh. Well, I really want to know now.

Jacob Trefethen:
If you're diabetic at home in the first half of the 20th century and you are married to someone who doesn't have your best interests at heart, it's not such a good combination, I'll leave it there.

Saloni Dattani:
I'll try to remember that.

Yeah, so where were we? I guess we were sort of in the 1940s to '60s at this point. What was just about to happen was major breakthrough. So in the 1970s, scientists were about to develop something called "recombinant DNA technology", and that would change everything — especially with diabetes — but it would also change biology.

So what is recombinant DNA technology? It's when you combine DNA from two organisms. In this case, what's happening is scientists figured out how to introduce the genes to produce insulin into bacteria — which means that bacteria would be producing the insulin and they could be used as little factories to produce it. So we wouldn't have to rely on the pancreases from animals.

These breakthroughs came from researchers at UC San Francisco, like Herbert Boyer, who had developed this method to clone a gene. And there were other researchers at the City of Hope Medical Research Centre like Arthur Riggs, Keiichi Itakura and David Goeddel. They applied this method, to clone a gene, to insulin. So essentially they're using the same amino acid sequence that produces insulin, but making the bacteria produce that instead.

Jacob Trefethen:
I see. So before the last fifty years, say, people needed insulin. Insulin's a protein, but we couldn't really make proteins in a systematic way, so we're taking 'em from animals. And then, with these breakthroughs starting about 50 years ago, there were some biotechnology innovations that allowed us to be more systematic about how we make 'em.

Saloni Dattani:
Right. But actually, you've kind of alluded to something very interesting, which is that this turned into the first- the kind of birth of the biotechnology industry as a whole. Because these researchers were able to develop, or modify, genetic material and get bacteria to produce it, and they could kind of engineer that. They spurred this whole industry of people doing that for different uses, but also a different type of model where researchers would not just be academics — they wouldn't just be working with other private companies or with the government to develop products — but they would actually spin out their research into something that could be a commercial product.

Jacob Trefethen:
Yeah.

Saloni Dattani:
So, Boyer spun out his research into a new company called "Genentech", with a venture capitalist called Robert Swanson. And they raised private funding for this project with this promise that they would be able to develop insulin from bacteria, and make it a much more efficient process.

But at the time, there was a big problem with doing this research. Recombinant DNA technology was seen as really dangerous. We were basically "meddling with the genetic code of life". Maybe we would be producing harmful proteins, and if bacteria were producing them, maybe they would produce too much of them, and we wouldn't know how to stop them, or control this process. So, in 1975, scientists came together for this conference and they recommended that there would be restrictions on the technology of recombinant DNA. They recommended high containment labs and a ban on some methods for a few years. But Genentech actually managed to avoid this, and one reason for that is that they actually didn't work with human genes. They didn't know the genetic code for human insulin at the time. All they knew was its amino acid sequence.

Jacob Trefethen:
Whoa. That's so strange to think. I'm so used to so much genetic information now. Wow.

Saloni Dattani:
Right. It's so easy for us to sequence the code for some genetic material now, but at the time it was difficult. All they knew was the amino acids. We have DNA or genetic code — the A, C, T, G — that gets turned into RNA and then gets turned into a chain of amino acids, which then folds up into a much larger structure, which could be a blobby shape of a protein.

In insulin, there are two of these chains of amino acid proteins that are linked up. What the researchers did was they produced each of these protein chains, based on their amino acid sequence in bacteria, separately. They basically thought in reverse: we have the amino acid sequence, what DNA would produce that? And specifically, what DNA would produce that in bacteria? And they got bacteria to produce these different chains, and then they joined them together in the lab to make the final insulin molecule.

These processes as well meant that they were avoiding the potential dangers that people associated with recombinant DNA technology. And it took a lot of hard work, but the researchers at Genentech, this startup, managed to produce some proteins. They produced somatostatin, which is a tiny hormone that regulates growth hormone and insulin in bacteria, in 1977, and that was a huge breakthrough, and they kind of used it as a pilot test. And then in 1978, they applied the same method to produce insulin in bacteria.

Jacob Trefethen:
So we have insulin from a bioreactor, not from an animal.

Saloni Dattani:
Right. We're basically churning out insulin proteins in a tank that's filled with bacteria. This is so interesting as well, because when I talked about how you would get insulin from the pancreases of animals — within the pancreas, only some 1% of cells produce insulin — but in bacteria in a tank that you've engineered, almost a hundred percent of the bacteria would be producing insulin.

Jacob Trefethen:
Right? Yeah, for sure. Yield!

Saloni Dattani:
It took them a while to figure out how to make that process efficient. But the fraction of bacteria producing insulin is much larger, and also, each bacterium was producing so much insulin. There was this amazing description that I read that each bacterium was producing so much insulin that they would kind of swell up like an olive or a tiny stuffed sack that was just full of insulin, which I found very funny.

Jacob Trefethen:
Very good.

Saloni Dattani:
So this breakthrough changed everything. Getting insulin to be produced by bacteria — having recombinant insulin — meant a much larger scope for production. Eli Lilly signed an agreement with Genentech to take this technology, and they asked them to find more efficient ways to scale up this whole process, and they eventually did. In 1982, insulin produced by bacteria, was taken through clinical trials and approved, and it was called Humulin. It was the first genetically engineered drug. And as I said, it was also the birth of the biotech industry, where academic researchers spin out their discoveries into startups, get venture capital to develop them into products, and then partner with big pharmaceutical companies to bring them to market.

Jacob Trefethen:
What an amazing drug. I am so grateful that we have insulin now, that you can make and that people who need it can take.

Saloni Dattani:
It's crazy to think about the difference, right? Because we now have this- that I guess I would not have even thought about what came before it. I don't know anyone who would've taken the treatment before — injecting themselves with these huge glass needles. There's this amazing book about the story that you recommended it to me a while ago and I read it and now I highly recommend it as well. It's called "Genentech: the Beginnings of Biotech" by Sally Smith Hughes and-

Jacob Trefethen:
Sally Smith Hughes.

Saloni Dattani:
-I actually have it right here. It's very, very good.

Jacob Trefethen:
Very good.

Saloni Dattani:
This wasn't even the end of the story, right? Okay, we now have insulin that's being produced by bacteria much more efficiently. But just a few years later, in 1985, Novo would develop insulin pens, which were a much easier way of taking insulin and getting immediate effects from it, than the older syringes. And if you think to now, maybe you know people with diabetes, sometimes they have these continuous insulin pumps that are attached to their skin and that deliver insulin to them throughout the day, whenever they need it, and there are also continuous glucose monitors.

I remember when I was young seeing my dad prick his finger to get a drop of his blood to be tested. But now there are continuous monitors for glucose that are also attached to your skin, and you can have new products that combine both of them together. So it's both monitoring the level of glucose in your blood and then also releasing insulin in response to that when you have food, to make these real-time adjustments into controlling blood sugar levels.

Jacob Trefethen:
So cool.

Saloni Dattani:
I think it's amazing, yeah. And even recombinant DNA technology didn't stop there. It's been used to make proteins and hormones for other kinds of diseases. One of them is to treat growth failure in kids. So you could use an enzyme or a hormone called "human growth hormone" and produce that in bacteria, and it was really important because before that the only way to get growth hormone was to extract it from the brains of cadavers. And that was dangerous because cadavers were sometimes contaminated with degenerative proteins that cause diseases like Creutzfeldt-Jakob disease, which is very scary.

Jacob Trefethen:
Well, you might be dealing with... 50% chance you're dealing with zombies at that point.

Saloni Dattani:
I've heard that recombinant DNA is now a very common research tool, used in almost all kinds of biology.

Jacob Trefethen:
It also has completely changed what research you can do. You can just 'grow up' a protein pretty easily in small batches. You don't even need a big bioreactor, and you can test out some stuff with it.

Saloni Dattani:
So, yes, there we have it: a century of insulin in 15 minutes. I hope you enjoyed this and I hope you like and subscribe and share this with all of your friends.

Jacob Trefethen:
Because next episode, we're going to talk about taking proteins nature has designed, like insulin and others, and improving upon them using new methods with artificial intelligence.

Saloni Dattani:
Nice.