Moonlight Science: A Conversation with Molecular Biologist and Entrepreneur, Paul Schimmel

This article was formerly published in Wild River Review as part of the Quark Park column.

by Kimberly Nagy

Quark Park Exhibit

I first met Paul Schimmel, a global expert in the fields of molecular biology, biochemistry and enzymology, on a sunny autumn day. We arranged to meet at Quark Park, an outdoor garden devoted to science and art. During our filmed interview we sat within an artistic representation of Schimmel’s research constructed by sculptor, Robert Canon. Within hanging fragments of mirrors, tiny letters that symbolized genetic processes spun in the sunlight. Their reflections created circling flickers of light and random word patterns, depending completely on the mood of the sun. It seemed the appropriate setting to talk about the origin, unpredictability, and connectedness of all life forms.

Paul Schimmel

Schimmel is the Ernst and Jean Han Professor of Molecular Biology and Chemistry at the Skaggs Institute for Chemical Biology at the Scripps Research Institute in Southern California. Before that he served as the John D. and Catherine T. MacArthur Professor of Biochemistry and Biophysics in the Department of Biology at MIT. In 2001, Nature Magazine listed Schimmel’s work as one of the developments that launched the Human Genome project.

Schimmel has spent most of his academic career unraveling the mysteries of the genetic code, particularly the tRNA synthetase family of enzymes. They are believed by many to be among the first enzymes to arise on this planet in the early stages of the evolution of life. But they also have direct relevance to our understanding and treatment of a wide range of diseases, from immune disorders to cancer.

Many years ago, when the rules of the genetic code were discovered, Schimmel was doing post-doctoral work at Stanford University and describes himself as a “harder-core” Physical Chemist during that time.

“The rules of the code were such a wonder to me, so compelling. Even then we could see that it was universal, of course, we understand that even better now. The idea was so grand and so spectacular, that I decided I wanted to connect myself to it,” Schimmel remembers.

The ubiquitous language and editing process that translates proteins into not just our eye and hair color, but allows for the translation between cell signaling and our bodily functions (like swallowing, walking and talking) allows little room for error.

“Life is on a razor’s edge,” says Schimmel, “we aren’t really aware of how much perfection is necessary to survive. It’s astonishing. For me, it creates a sense of reverence.”

Warm and humble, Schimmel is the kind of person who can shrug off such hard truths with a smile. “Even though I can’t possibly pretend to have a mind that grasps all of this, there are experiments that can be done. There are avenues of research which are a source of fulfillment to me at least.”

But, Schimmel is more than a scientist committed to moving important research forward, he is also a successful businessman. Voted Most Entrepreneurial Scientist of the Year in 2007, Schimmel has been lauded for being a founding director of 11 companies, including a company called Alkermes which produces new delivery methods for drugs, such as risperdal used in the treatment of schizophrenia. Four of his companies have been sold and six are publicly traded, with the newest one still privately held.

In our interview, Schimmel and I continued our conversation about the origin of life, the thrill of scientific discovery, the importance of collaboration, the latest trends in global technology, and the laws of survival that govern scientists and businesses alike. Schimmel reminds me that evolution does not so much mean survival of the “strongest or the fittest” but rather the ones most adaptive to inevitable change.

WRR: Can you talk about one of your most memorable moments of scientific discovery?

Back in the late 1980s, when we had a young woman in the laboratory, Ya-Ming Hou, we found something that suggested that the genetic code had a precursor and wrote a paper about it, which a brilliant Rockefeller University scientist Christian de Duve saw. In many ways, he might have seen it more clearly than we did. In turn, he wrote a piece for Nature, citing our work as an example of what he believed showed that there was a second or more primitive genetic code that preceded the existing genetic code.

After that, we focused very much on trying to understand this so-called second genetic code. And that has been an incredible adventure, one that has led us to get more and more at the roots, the origins of the code we have today, originating in yet another more primitive code that came out of what we call the RNA world.

Eventually it’s made it possible to create proteins out of RNA information, so that we now think information processing and transfer started with a more primitive code. That was highly memorable.

WRR: How do you study this code?

Well, another memorable event was when we discovered a mechanism by which the code was made more perfect and this is important. A couple of years ago we published a paper in Nature showing that in animals even the slightest imperfection in code can lead to serious disease.

We realized that this mechanism, worked out in detail originally by one of my first graduate students (who followed up on a study from Stanford in the Paul Berg’s laboratory) was not a nearly exact code. It had to be nearly perfect every time. That was something that really excited us as we worked out all of those details over the last many decades, particularly the last ten years. And Alan Fersht in England, Yarus in Boulder, and groups in Japan like those of Yokoyama and Nureki and groups in France like those of Giegé and Cusack all contributed mightily.

WRR: Can you talk a little bit more about how you discovered that a slight imperfection in the genetic code could actually translate into disease. What kind of diseases?

In one case, we worked with the Jackson laboratory. They’re very interested in neurological disorders, diseases of the brain, diseases that cause difficulty in walking, problems with your peripheral neurons, the neurons that feed your legs. What we learned is that slight imperfections in decoding genetic information leads to proteins that contain error and, as a result, serious degeneration to parts of the brain occur, resulting in difficulties in walking, for example.

We are virtually certain that if we make the defect more pronounced, it will result in death. We captured the mildest defect in this process, called the editing process. This editing system is really designed to clean up the code, and come back and take a second pass and say, “is this really correct?” But when that editing process gets off a little bit, sometimes errors get through, and they result in proteins that are imperfect. Those imperfect proteins are sufficient in this case to lead to various neurological problems.

The performance of body parts and the brain and the ability to move around and ultimately, if it’s more severe, can lead to degeneration and death. At the same time, in the positive way of that, it means that we are products of a million years of evolution in which this system really got perfected.

WRR: Talk a little more about this “moonlight life,” the discovery of our secret life.

We have long investigated ancient proteins for their role in establishing the rules of the genetic code. And we discovered that these proteins also have other lives…they moonlight as players in signal transduction pathways that have nothing to do with their original purpose (which they still carry out)…these moonlighting activities have many connections with disease and potential therapies, so we are quite excited about them.

Schimmel Laboratory

Schimmel Laboratory

WRR: We often equate scientific discovery to one person such as Darwin or Einstein…but in reality there are often many people involved, research digested and transformed into new discoveries? Can you talk about the importance of collaboration?

Adaptation really comes from collaboration. Survival does not go to the strongest or fittest, but those who can best adapt to change. Being flexible is crucial. It is often not the companies that have the most money or knowledge, but those who can adapt to change and be flexible and take research in different directions. It is often the scientist who can let go of their most cherished ideas, those who can collaborate and make sure their research and ideas are relevant on a wider scale, who will ultimately make a difference.

Most scientists are used to being in a very protective environment. Once they step outside that world or try to connect that world to the outside business world, you really have a lot to adapt to. The very talented businessperson and scientist is a rare person. To an extent I’ve enjoyed success because I’ve become aligned with business leadership that makes sense for my research. Without these people, I would not have had the commercial success I have enjoyed.

WRR: You won the Most Entrepreneurial Scientist of the Year award in 2007. How do you see the relationship between entrepreneurship and science?

I think that it’s fairly difficult to transfer science out of the university. In my case, I’ve been able to work with lots of people who are skilled with that interface, people with a lot of experience developing new technologies, people who can see what works for treating human diseases and who work both inside and outside the university.

We have many wonderful discoveries, but we also know many of those discoveries can not translate into therapeutics without that outside help.

I have started a large number of companies, but I know I never could have done any of that without help. In my view, it’s important to see what you’re good at, but also to know your limits. Knowing when to let something you discovered and are excited about should be explored further and knowing when to let your own ideas go.

WRR: Where do you see the future of biotechnology in our global economy? Where does the majority of research take place and why? I say this because I believe many research scientists are now based out of China?

What’s happened in the US is that the larger and larger portion of the PhDs that are produced in the US are coming from foreign countries…People have analyzed this, and there is much written about it, but basically the idea is that a large percentage of the foreign students today are populating the laboratories. These folks are the ones who are getting PhDs. For me, I see this happening more and more not only here in California, but throughout the country. I think it’s something that we just have to face up to and is a reality in many fields of science and engineering. The truth is high tech employers are very dependant on these scientists and engineers.

The best science students now are coming out of Asia. Fewer and fewer advanced students are coming out of the US. So, I’m doing some of the work in Hong Kong and some in San Diego. For me, as a scientist who really wants to see important research move forward, going to Hong Kong and China, makes all the sense in the world because of the tremendous support you get from the government there and the enormous, motivated, talented pool of young scientists that you have there.

Investing in human health and the knowledge industry is a great investment for American taxpayers. We are paid back in human health and economic improvement. I like to think I’m a part of that process of people being paid back.

But venture capital is a unique enterprise in the US. There are more and more efforts to develop that infrastructure, and to catalyze it in Europe. Look at companies like Google or Intel or many biotech companies. It is possible to start all of these companies just because of the environment.

WRR: Some people view technology with suspicion, especially when it comes to cells or our brains, as research might not always be used to “good” ends, what are your views on this?

Well, I think that human beings were evolved and created with an innate curiosity. Some people have it more than others.

Once an idea comes out of a human head, it will be pursued. The question is how it is pursued. Will it be pursued in the light of day? Will it be pursued in a thoughtful dialogue with society? In pursuing these questions, we learn about life. At the same time, there are many limits to our intelligence.

WRR: How do you see these limits?

If you had talked, for instance, to Ben Franklin and asked whether it would have been possible for a person in America to talk to sometime (in real time) in the Orient, he would have said NO, that cannot happen. There is no scientific law that tells us that can happen.’

Nevertheless, today if you and I are having a conversation in the same building, but we are 200 feet apart, someone on the other side of my cell phone connection in Singapore will hear my voice before you will. My voice is traveling at the speed of light, but to you in the same building, it is traveling at the speed of sound. Now, if you had said that to someone back in the 1700s, they would consider that a miracle. What you have to say is that whatever knowledge we have, the next breakthroughs will probably not come through something incrementally…but it will come all of a sudden and will open up a whole new area of science.

But, we’re very limited by our brains. It’s like a machine trying to understand itself. Epiphany, leaping to new levels of understanding, is driven by that same curiosity we just discussed. We can’t predict what’s next but in the future we might begin to find a better understanding of ourselves.

Schimmel at age five

Schimmel at age five