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Making inroads into rational protein design

Daniel Schmidt invents high-precision optogenetic reagents to investigate fundamental mechanisms of cellular signaling.

Daniel Schmidt

New technologies have allowed biology to progress from a science based on observation and description to a discipline that routinely reshapes living systems through deliberate design choices. Daniel Schmidt, new faculty in Genetics, Cell Biology and Development hired as part of the Cellular Biophysics research cluster, aims to ignite new waves of discovery by inventing ever more precise tools for the engineering of biology.

Biologists across the globe work to gain insight into the fundamental rules of life. It is difficult, however, to test hypotheses in natural systems that cannot be precisely controlled. Schmidt’s goal is to engineer artificial living systems, and by recording what works and what doesn’t, ultimately deduce the mechanisms that govern cellular life.

Trained in biochemistry and neuroscience at Rockefeller University and MIT, Schmidt combines skills from biochemistry, biophysics and neural engineering to achieve this goal. At the U of M, he plans not only to develop groundbreaking techniques in rational protein design, but also to begin unraveling the mysteries of cellular signaling.

Learn about intriguing new avenues in molecular research—and how they could translate to the clinic—in the Q&A below.

As you begin your work here at the U of M, what is your fundamental goal?

“Ultimately, we are trying to enable progress in maintaining human health. For many disorders, we do not fully understand the underlying biology, often because we simply don't have the experimental inroads necessary to set up experiments that will give us meaningful answers.

Right now, we see the need to invent precision molecular tools to perturb cellular signaling. We also need better delivery methods for our technologies so that they end up in the right cells. Our team focuses on these two goals because we believe that they will enable fundamentally new kinds of experiments and studies—but over time, our mission can change. In fact, it has to change.”

Why must your lab’s mission change?

We are applying our inventions to unsolved questions in biology and medicine. Tools cannot exist in a purpose-free space. We must provide a philosophy for how to use them and constantly evaluate their utility and impact. As we make new discoveries, we will slowly but surely improve our understanding of cellular signaling. With new understanding comes new questions, and those questions might be best addressed using a completely different strategy than we use today. We have to keep an open mind and be willing to also reinvent ourselves.

Do you model disease in any particular organism?

We choose the model that is most appropriate for the problem in the realm of cellular signaling that we are trying to solve, and—again—this choice changes over time. For example, we can study altered ion channel homeostasis in cultured neurons, psychiatric disorders like epilepsy and heart rhythm disorders like long-QT syndrome in zebrafish, and cancers in induced pluripotent stem cells. The power of yeast genetics can be combined with directed evolution to address fundamental questions in protein engineering. The U of M advantage is that there is expertise in all of these model systems and many research groups work on very diverse sets of problems with immediate translational potential. We consider all them potential collaborators.

In classical optogenetics, neurons can be turned “on” or “off” using light—a form of binary control achieved by two engineered proteins. How do your optogenetic tools differ?

If you examine the underlying electrophysiology, you find that the computation in a neuron is achieved through the concerted activity of many different ion channels and receptors. For neuronal signaling, it not only matters whether a neuron is active or silent, but the quality of the signal, how it's computed, is important as well. Our technology enables analog control in neurons, because we use molecular reagents called lumitoxins that target specific channels and specific receptors which can be modulated with light.

Why is it necessary to use artificial rather than natural systems to develop these optogenetic reagents?

With artificial systems, you can explore the space of possibilities not found in nature. For example, lumitoxins are synthetic fusion proteins in which we have combined disparate input and output domains: a human membrane protein, a photoreceptor from a plant, and a spider venom toxin. Our proteins are rationally designed, which makes them interesting not just for what they do as analog modulators of an activity, but it also makes them interesting from a pure protein engineering perspective. For now, rational protein engineering is almost an art form, we have to try and fail many times before we create something truly functional. With time, however, we can synthesize a deeper understanding of protein architecture and function from these trials and errors—perhaps a universal design language and a set of well understood, standardized parts.

Once you’ve developed these chimeric proteins, how do you express them in live animals?

Viral delivery is a mainstay for delivering genetic payloads into living organism, but the limiting factor there is that you're governed by the natural tropism of the virus. Tropism refers to what tissues and cells the virus targets naturally. Many viruses have a very broad tropism, so that many tissues get transduced very efficiently. We want to develop delivery technologies that do away with the limit of viral tropism and allow us to infect any tissue and cell types we choose. We consider this very important with respect to making inroads in human gene therapy.

Does this mean we should expect to see optogenetics in future gene therapies?

It's not necessary to use light in a clinical setting. We use light in a laboratory setting because it's easy to dose and deliver. It is more important to understand the principles of genetic and cellular engineering that are the foundation for a successful gene therapy. Once we have developed the genetic circuitry that affects a treated tissue in the desired way, we can replace a light switch with another switch sensitive to, for example, an endogenous metabolite or highly bioavailable drug. So, the patient still takes a pill. The difference is, that pill will not be a chemical that bathes your brain and affects all the cells indiscriminately. That chemical will affect only cells that carry a genetic program, which you can deliver to a specific set of cells using a precision delivery technology.

You describe this almost like parts that can be mixed and matched.

Indeed, biology is very modular and we just started with the easiest building blocks. It’s an incredibly exciting time; in just a few years all of what we do today will seem rudimentary. I’m very optimistic that biologically-inspired engineering will give medical technology and disease treatment a much broader meaning.

– Colleen Smith


Posted 4/8/15