Inside the Second Genetic Code: An Interview with Paul Schimmel

For nearly 50 years, translational medicine pioneer Paul Schimmel, who is Ernest and Jean Hahn Professor and member of The Skaggs Institute for Chemical Biology and The Scripps Laboratories for tRNA Synthetase Research at The Scripps Research Institute (TSRI), has focused on a group of universal enzymes believed to be one of the first to arise on earth during the early stages of the evolution of life—the 20 aminoacyl tRNA synthetases, which interpret genetic information in all living organisms. Today, his lab continues to focus on these enzymes, going beyond the genetic code to the surprising expanded functions they have acquired during evolution, and their therapeutic uses. Recently, he sat down with Padma Nagappan of News&Views to discuss how he got to this point and what his lab is working on now.

News&Views: How did you choose a research area?

Schimmel: I was a postdoctoral fellow at Stanford, focused on theoretical work, when what I will always feel was the greatest discovery of the 20^st century was made—the genetic code. This changed everything and biology went from a descriptive to a molecular science. It helped place us on the Tree of Life. I was so riveted that I decided to work on the code, its universality, and how it was established at the biochemical level.

Whether you are talking about a creature who lives in the subthermal vents in the deep seas, like tube worms, the nine-armed Pacific octopus, cyanobacteria that can grow at near-boiling water temperatures, flowers, butterflies or timber wolves, they are all possible because of the same genetic code, and this is staggering. The code is so powerful and robust that it obliterated all other competing codes and gave us enormous diversity.

When I realized the code is really a simple algorithm that assigns the order of nucleotides that make up the genes (in the DNA of each cell) to each of the 20 amino acids, I decided to work on it. My interest was in the tRNA synthetases, because they are the 20 agents that give each of the 20 amino acids their proper assignment to a snippet of DNA. Most profound to me was that, starting with the last universal ancestor of all life (which is like the root of a tree), this algorithm led over the eons to the enormous Tree of Life with all of its diversity. The Tree can be thought of as a vast array of ascending branches, with humans being the highest “shoot” or branch.  I decided to work on it. When I left Stanford to go to MIT, they were expecting a pure biophysicist, but instead they got something different. The synthetases have occupied me ever since.

News&Views: Not many people understand what you do. Can you explain it in simple terms?

Schimmel: Well, as stated, we work with the agents that decode genetic information—the enzymes that interpret your genes. They're fundamental. My first significant contribution was learning and publishing how they do this with extraordinary accuracy. This is important because cells cannot deal with inaccuracy. Big defects in accuracy can be fatal and just minor defects have been shown to lead to a deteriorated nervous system.

The next thing we did, which received a lot of attention, was to discover what some refer to as the “second genetic code.” That work gave strong support to the idea that there was a primitive code (perhaps over 2 billion years ago) before the present-day genetic code became firmly established. This second genetic code is fundamental and has a critical role in determining the algorithm of the present-day modern genetic code.

Later, we went on to discover in 1999 that there was a whole new life these proteins had in human cells, which had been mostly missed. This “new life” is represented by novel functions they acquired in evolution, which are quite distinct from those associated with their traditional role of decoding, or interpreting, genetic information. These novel functions have led us to a new deep layer of biology, which will take years to work on.

News&Views: The proteins have functions that go beyond interpreting the code?

Schimmel: Yes, what I am saying is that not only do they establish the genetic code, but also they go beyond that; they have acquired new functions for building the great Tree of Life. Our focus now is on the functions that help them implement and modify immune responses, build vascular and nervous systems, and control cell growth—it’s a whole new field of biology just now emerging, showing us new connections very different from what we knew before.

News&Views: What are some potential therapeutic applications?

Schimmel: One potential application that will go to human clinical trials this year is for inflammatory muscle weakness—polymyositis—which over time can migrate to the lungs and eventually lead to death. The condition has a significant link to the mechanism of one of the 20 tRNA synthetases and we believe we can treat it with a medicine derived from that specific tRNA synthetase.

Life is really about tipping points. When people have polymyositis, we believe we can tickle this tipping point and reestablish homeostasis (equilibrium). It’s like you’re wobbling on a seesaw and we can now intervene to reestablish balance.

This is probably the first therapeutic application of these novel functions. We also have seen some beautiful data in mice for inflammatory bowel disease. We can use a piece of a tRNA synthetase to ameliorate this condition in a mouse. So it could be used as a drug for the condition.

There are also applications in cancer—two of our synthetases are strong in either blocking the formation of new blood vessels around tumors or in stopping the signals that promote aggressive tumor growth. We're very excited. This is something that means a lot to me. I’ve transferred a lot of research to biotech companies over the years, and now we're getting examples of how this can save lives.

News&Views: How will this knowledge influence how drugs target diseases?

Schimmel: Natural pieces of tRNA synthetases will be medicines. This area also opens up huge opportunities to discover drug targets and how they work—Phil Baran or Dale Boger or Barry Sharpless or Jin-Quan Yu or someone else at Scripps may eventually make chemical mimics.

News&Views: Tell us about your lab.

Schimmel: We’ve pooled our physical resources with Associate Professor Xiang-Lei Yang because of our mutual research interests. We also are close to Assistant Professor Min Guo at Scripps Florida. The three laboratories make up The Scripps Laboratories for tRNA Synthetase Research. We each have separate grants and we’re independent investigators. Altogether we have about 20 researchers here in the US and another 5 in Hong Kong, where The Scripps Research Institute has an arrangement with the Hong Kong University of Science and Technology.

News&Views: What is your lab working on now?

Schimmel: I’m very interested in the diseases caused by the errors and inaccuracies of decoding genetic information—errors of decoding can lead in a curious way to changes in the genes in specific tissues, like liver, spleen, brain and lung. This is a situation where we can get mutations or errors in the DNA caused by errors made by tRNA synthetases while they are directing the synthesis of proteins.

The other thing I’m looking at is how the errors are related to autoimmune diseases like multiple sclerosis. For example, we're interested in how what you eat can cause mistakes in cellular proteins that over time can lead to an autoimmune condition.

We’re further interested in uncovering more about the interacting partners of tRNA synthetases in a cell and how these partners are connected to diseases. Also, we believe we can make connections to aging and actually slow down the process—because, in principle, you should be able to slow the rate at which you age by the proper exploitation of the mechanisms associated with these marvelous enzymes.

News&Views: You’ve seen research funding change quite a bit over your career.

Schimmel:  It has changed dramatically. I’m very grateful for all the support I have received from NIH over the years, but today there is a lot of pressure to focus on priorities the government has identified. This paradigm shift occurred in Europe and, I feel, was not beneficial to discovery research. The work I do would be hard to find support for in Europe.

In contrast, the support we have received from private foundations has given us a lot of freedom. One night I was at a meeting in New York and an elderly woman sat down and told me that she ran a small foundation with her husband. They didn’t have the resources to vet applications, so their goal was to do the best they could for society with the funds they had. The best filter they had was to find those who were doing outstanding work and didn't need money. She said, “We've identified you and want to help you to do research even more at ‘the edge’”

Years later when I was recruited by Scripps, I think the Skaggs family felt the same way. Members of the Skaggs family knew they could not identify specific areas that were promising, but they could identify the people who would—that’s a wonderful thing and I’ve never forgotten it. Our first discovery of the expanded function of a human tRNA synthetase was by a Japanese postdoctoral fellow who was facilitated by these funds.

News&Views: What are you most proud of that your lab here has achieved?

Schimmel: That's a hard question. There are two things very close to my heart—one is the discovery of a major mechanism for accurately decoding genetic information and its relevance for health and disease. Second is the discovery of the new functions of the tRNA synthetases and their relevance to disease.

Thirdly, I’m very proud of the work we did that established what became known as ESTs (expressed sequence tags) and the technique of shotgun sequencing (a key development in 1983 that Nature magazine cited as one of the major foundations for the launching of the human genome project). Several years after we developed the technology, Venter did a great job of industrializing it. The technique developed by us was actually a side project, because we were under pressure to solve a problem we couldn’t solve—so we invented the technology for that purpose. It worked far beyond our imagination and had broad impact. For many years after we had developed the methodology, people contacted us to help them harvest its fruits. I found that kind of contribution to the community to be quite meaningful.

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