Art Riggs: The story behind synthetic human insulin

June 3, 2013 | by

As City of Hope celebrates its 100th anniversary, we offer a four-part interview with Art Riggs, Ph.D., chair of the Department of Diabetes and Metabolic Diseases Research. Many of City of Hope’s best-known breakthroughs came through his lab. In this series, he casts an eye back to some of his greatest scientific contributions — and forward to the advances on the horizon.

The science that led to synthetic human insulin began with Art Riggs' curiosity about how to turn genes on and off. (Photo: Walter Urie)

The science that led to synthetic human insulin began with Art Riggs' curiosity about how to turn genes on and off. (Photo: Walter Urie)

In Part 2, Riggs talks about his work that led to synthetic human insulin. This medicine is now used by millions of diabetes patients all over the world to manage their disease.

In the late 1970s, you worked with City of Hope biologist Keiichi Itakura, Ph.D., and scientists at Genentech to coax E. coli, that familiar gut bacteria, to produce human hormones. One resulting drug, synthetic human insulin, certainly has had a huge impact on the treatment of diabetes. It can be considered as having launched the biotechnology industry, because it was the first product of biotechnology approved by the Food and Drug Administration. For a project that had such broad impact, what were the questions that started you down that path?

For me, it was questions about how genes are turned on and off. I was very interested in how genes are turned on and off in a very precise program: How can you program genes so they come on when they need to be on and they go off when they don’t need to be on? That’s the question I was interested in.

Art Riggs on recombinant DNA:
“The best analogy for DNA is a strip of magnetic tape, like in a cassette. For the next generation we must come up with some other way of describing it, but the best analogy is with a cassette tape.

“A cassette tape has the instructions for playing the music. It has a beginning and an end, and there’s a code that says: With this code you have this tone. One bit will tell you what note to play and the next bit will tell you another note.

“DNA is very much like that. When you take a gene from a mouse and put it into a bacterial gene, you cut out a piece of the mouse tape and you put it into the bacterial tape. So you cut and splice. Recombinant DNA technology is just how to cut and splice and put genes where you want them.”

When I was a postdoc at the Salk Institute, I worked on how genes are turned off by a certain protein. I worked on the first transcription factor, which was called the lac repressor. That was a protein that sits on the DNA and turns off a gene called β-galactosidase. It allows us to use the lactose that’s in milk; if our guts don’t produce β-galactosidase, we can’t drink milk without a lot of intestinal problems.

My interest was primarily as a physical chemist. I was interested in studying that chemical interaction.

About 1974 we got a letter from Itakura saying that he was looking for a job and that he could synthesize the DNA that the repressor binds to. That led to him coming to City of Hope. And that led to a project with a professor at Caltech. We were trying to get a crystal of the repressor — it’s just pure physical chemistry.

At some point, the details of that project led us into the use of chemically synthesized DNA in cloning. At that time, cloning using recombinant enzymes was being discovered by Herb Boyer [then a biochemist at the University of California, San Francisco] among others.

Herb Boyer was a friend of mine. We collaborated with Herb Boyer, and we improved the methodology for recombinant DNA. Those were major contributions.

What we did was combine two technologies. We combined the chemical DNA synthesis technology and the recombinant DNA technology. There may have been a couple other groups trying this around the world, but we were the first to be successful in combining the two technologies.

We published with Herb Boyer and Herbert Heyneker [then a postdoctoral fellow in Boyer’s lab]. We used the technology that Itakura was the master of to make small pieces of DNA, which greatly improved the ability to cut and splice exactly where you wanted. We devised how you can put them exactly where you want them — something you couldn’t quite do prior to that.

That was a major contribution. It’s called “linker technology.” It became universally used in the field, but we didn’t patent it. We didn’t think about it at the time.

The public focus is on insulin and so forth, but the technical breakthroughs included the linker technology. We made recombinant DNA much more rapid, much more flexible.  That enabled the entire field of molecular biology to leap forward. So it really was transformational.

In ’74, ’75, we had shown that Itakura could make good DNA. So he and I started thinking: What would be the next project? We did think seriously about insulin. It was something we thought was within the realm of possibility. We also knew it was a challenge.

Itakura and I decided to start with a smaller hormone, called somatostatin. We submitted a grant application to the National Institutes of Health to do that project.

More or less at the same time, I got a phone call from Herb Boyer. He said, “Art, I have this businessman friend of mine who thinks that he can start a company based on recombinant DNA. We would like the first product to be insulin. Would you and Itakura be interested in having a contract with Genentech to do the work?”

I said, “Yes, of course. But we’ve already submitted a grant and I think we should start with something simpler first.”

It turned out to be a rather difficult task. One of my important contributions was to be an advocate for doing something simple first. Somatostatin was only 14 amino acids, about one-tenth the size of insulin. I was successful in convincing Herb Boyer and his partner, Robert Swanson, that we needed to establish the technology first.

The grant application was turned down as being unrealistic. The sentence I liked the best, which is a direct quote, is, “It seems like just an intellectual exercise.” So they turned it down and said it was not practical to do it.

So we worked with Herb Boyer and took the contract from Genentech. That was a fantastic project. About one year after we started, we had tricked the bacteria into making human somatostatin. And then a year after that, we successfully got them to make human insulin.

And it all started with the basic question about how to turn genes on and off.