Stephen Fuchs is an Assistant Professor of Biology at Tufts University. His research lies at the interface of chemistry, biology, and genetics. Dr. Fuchs works with model organisms—specifically yeast—and is interested in understanding the relationship between a protein’s three-dimensional structure and its function. This interview has been edited and condensed from the original.
Semper Curious: Let’s start broad. What counts as a biological problem or question?
Stephen Fuchs: For us, a biological question is anything having to do with the biological world: How an organism develops, how an organism exists, how it interacts with its environment, whatever that might be.
You can ask and answer biological questions from a number of perspectives. You can think of it truly from a biological perspective, thinking about the relationship between organisms, or within a certain framework of a cell, or what’s going on with multiple cells, tissues, organs, and so on.
The choice that I made—and there’s a lot of us that do this—we think of things much more at the bits and pieces, or nuts and bolts level, which is more of a chemical level. We’re thinking more about structures and how things actually interact, as well as what chemistries are going on or could be going on. You can also take this to a physical level, think about it using physical principles, and ask and answer the same questions. Chemistry and physics are, of course, intertwined, so what we learn about the chemistry is often related to the physics as well.
My lab is somewhat unique in that we try to use all of these approaches (chemical, biological, and physical), at least at some level. While lots of labs will choose one tool and dig deeper into their biological questions, we go the opposite way. We use many tools to look at very specific questions.
We’re growing mostly yeast, a single-celled organism, because it’s easy to work with and inexpensive to grow—but while it is an organism, we’re thinking about the chemistry that’s going on inside of it.
SC: How do you connect the goings-on at the chemical level to issues at the whole-organism level? For example, quantum physics and classical Newtonian physics are both successful at explaining physical behavior at their respective scales, but a successful integration of the two has remained elusive for physicists. Are there similar challenges here?
SF: Yeah, that’s a great example. If we’re thinking about a specific process, if we’re building it chemically, or studying it chemically, then we expect that if we were to measure what effect is happening as a function of time, then we can measure that usually with 99% accuracy at the chemical level.
But the difference between the chemical level and the biological level is—if you’re looking at what happens, for example, when you treat a developing tadpole with a drug, then maybe you get an effect just 80% or 85% of the time. The noise is much greater because the system is much more complex.
We can narrow our approach down to look at one particular pathway or one particular enzyme. Whereas in the biological case, you always have all of the things simultaneously interfering, in a sense.
SC: I imagine there are a number of steps between what you’re studying in yeast and some of these messier, more complex systems. Are the questions you’re asking applicable to both levels?
SF: Here’s a simple way to think about some of the problems that we’re trying to deal with. Our individual genes might be different, and the effects we’re measuring might be more subtle, but it’s just as straightforward as asking why—when certain people take a particular drug—it works, and with certain other people it doesn’t. We’re looking at small changes within a gene, and how that affects its function.
We know that many diseases are caused by a single mutation in a gene—like sickle-cell anemia, or cystic fibrosis. In these cases you’ve got a single genetic change that affects the function of the protein product, and that leads to altered biology.
We’re trying to understand, in my lab, some of what we call hidden genetic diversity, that explains the differences between individuals. So, the noise that we see at the biological level, how well a person responds to a particular treatment, maybe—where does that come from? What are the real players that are important for that difference?
SC: How novel is this approach? How far back would we have to go before we couldn’t ask the questions you’re asking, and wouldn’t have available the techniques you’re using to answer them?
SF: We’ve known about the structure of DNA for almost seventy years, and we’ve known that genetic diseases can be linked to hereditary changes for a hundred years. Some of the yeast techniques that we’re using go back thirty or forty years, but the newer techniques give us a scale that we didn’t have before.
One of the advantages of yeast is that everything we’re doing with yeast applies to humans, but it’s just a simpler system. Things go faster, and the genetics is easier to comprehend.
SC: It’s kind of distressing that everything that applies to yeast also applies to humans.
SF: Well—only when we’re thinking about the behavior of single cells. Once you get to the physiological issues, that’s a different question. But that’s why we’re looking at the chemical level.
You can read more about The Fuchs Lab here.
Stephen Fuchs
is Assistant Professor of Biology at Tufts University. He earned his BS in chemistry from Penn State University in 1999 and completed his Ph.D in Biochemistry at the University of Wisconsin–Madison in 2006. His research has been funded by NIH, the Army Research Office, and the Paul G. Allen Family Foundation.