Planning Out New Pathways

Michael Smanski aims to engineer synthetic biochemical pathways and fine-tune small molecule production for industrial applications.

We’re in the midst of a revolution in the life sciences and Michael Smanski is thrilled to be riding along the cutting edge right here at the University of Minnesota.

Smanksi joined the College of Biological Sciences this fall as assistant professor in the BioTechnology Institute and the Department of Biochemistry, Molecular Biology, and Biophysics. Hailing from MIT, Smanski’s expertise zooms in on the synthetic pathways that create small molecules known as “natural products.”

Natural products are specialized metabolites that are not required for growth or reproduction in the organisms that make them, but they have diverse—and often poorly understood—properties that make them prime targets for industrial bioengineering efforts.

Every time you smell the roses, you’re getting up close and personal with natural products. Beyond aromas and flavors, some of these remarkable molecules even sport powerful antibiotic or anticancer effects.

For decades, scientists have been studying and engineering natural products for use in agriculture, food and medicine, but they’ve been limited by tedious and slow technologies for manipulating these systems at a genetic level. Today’s technologies offer dramatically increased throughputs and vastly improved analytical tools.

There’s a lively buzz in the air at Smanski’s new lab as he prepares to investigate new questions about life at the molecular level. But before he gets going, we’ve got a few questions for him.

What’s so exciting about being a biologist the right now?

The decreasing costs for DNA synthesis are enabling us to step away from the traditional role of biology as a merely descriptive science. We can explore more ‘what if’ questions by building and studying synthetic genetic systems. I am excited in the near and distant future to see what novel insights into our living world will be enabled using these new technologies.

What plans do you have for your new lab here at the University of Minnesota?

There are two fields that I hope to bring together in my research: One is natural product biosynthesis, the other is synthetic biology. In my lab, we will comb through the thousands of available genome sequences to discover genes encoding the production of new small molecules. We will then leverage the latest synthetic DNA technologies to ‘build to understand’ how and why these molecules are produced.

How does this type of work differ from traditional biotech approaches?

The vast majority of today’s biotechnology applications rely on the expression of a single gene. Take insulin, for example. The insulin protein is encoded by a single gene, can be produced in a bacterium rather simply, and purified out of culture. The intracellular assembly lines that produce most small molecules, however, require dozens of gene products working together in unison. We are currently developing new methods that will greatly expand the scale of engineering these multi-gene systems. We’ll be able to build thousands of variants to better understand how aspects of genetic design affect their performance in live organisms. That's something that's never been done before in the natural products field.

What kind of organisms do you intend to study?

In the field of synthetic biology, people have primarily worked on standard model systems like the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae. In the past 10 years, we've made some stunning achievements in being able to precisely engineer gene expression in those organisms. The problem is, those tools and strategies aren't always directly portable to more industrially relevant organisms. One of my goals is to develop synthetic biology in Streptomyces; to bring a lot of these tools and strategies into a whole new group of organisms.

How about the natural products themselves—do you have any particular targets in mind?

Many researchers are looking at antibiotic and anticancer natural products. I take a special interest in neuroactive natural products. Fewer are looking at these, and they would be useful not only as neuroscience tools for interrogating neurobiology, but also as potential lead compounds in looking for new therapeutics for neurodegenerative disorders.

So, what drew you to the University of Minnesota?

I think the University of Minnesota is perfectly positioned to emerge as a national and international leader in the growing field of synthetic biology. The U has a tremendous history of applied microbiological research, spanning from drug discovery efforts to environmental bio-remediation to food and energy production. It offers high-quality resources to perform cutting-edge research, and the large campus is home to experts in just about everything. Most importantly though, the undergraduate and graduate programs at this university attract some of the best students I have seen.

You came for the students?!

The students play a critical role in the research that is done here. They’re the ones on the front lines, doing the research, running the experiments, making the discoveries. When you have great students, you can propose moonshot ideas and have a reasonable chance of them working. It's not just manpower, it's brainpower, it's creativity, it's being bold enough to try risky projects. That's the most important thing to succeed. None of it would be accomplished if you just had all the professors on campus without the students.

Have you learned anything fun here at the U so far?

When I interviewed here in February 2014, one of my eyelids froze shut walking between buildings. I did not know that could happen!

– Colleen Smith