Q&A with Michael Freeman

New BTI faculty member translates unknown microbial languages into novel possibilities for biotech.

By Colleen Smith

Michael Freeman joins the Biotechnology Institute this Spring as a new faculty in the College of Biological Sciences. Hired in the Synthetic Biology Cluster, Freeman specializes in the biosynthetic pathways that produce small molecules called natural products.

Natural products are molecules often manufactured by microbes, and they come in many different shapes and sizes. In human health, these biomolecules are of interest for their potential uses as new antibiotics or anticancer drugs. In microbial ecosystems, they also serve many other functions — most of which are presently undefined.

At the University of Minnesota, Freeman will target intriguing bacteria that have not previously been cultured or easily manipulated in the laboratory setting. By studying unknown — and often remarkable — microorganisms, Freeman’s work could lead down new avenues in biotech.

What fundamental question motivates your research?

“Microbes are vitally linked to human health. They live in the soil, affecting how our food grows. They live in our guts, affecting how we digest our food. Yet despite their importance, we still don’t know much about which bacteria are present in these different environments, what they are doing, or how they communicate. My main motivation is to learn how bacteria communicate with each other and the outside world.

With all the genomic sequencing data that is coming out now, my research builds on the idea that we now have a new window into microbial metabolisms. In particular, I’m interested in how microbes communicate with each other through the language of natural products. I focus on the way bacteria construct that language.”

When you say language, what do you mean?

“Well, I’m trying to convey a simple definition of language as a series of words that are built by a sequence of letters. One type of bacterial language is constructed of ‘words’ called peptides, a class of natural products. Peptides are made with amino acid ‘letters’ — each of which must be synthesized by the microbe in a very specific way. Understanding this language, and how to manipulate it, is really the holy grail.”

Do all microbes or bacteria use the same type of communication?

“Bacteria speak many different languages. Some are constructed with novel ‘letters,’ which imply new functions and new chemistry as a product of evolution. Others share common letters or words, even if they’re from completely different environments. However, we don’t always know which bacteria is speaking which language — and even if we do, we don’t know anything about how they are doing it. That’s the puzzle we’re trying to solve.”

Enzymes are specialized proteins that catalyze chemical reactions within living organisms. Why does it matter that uncultured bacteria can use strange enzymes to produce new letters?

“Most organisms use 20 letters for speaking the language of peptides. New enzyme functions essentially expand this number to create drastically more complex words and thus, a richer language. Functionally, these enzyme modifications affect the shape and behavior of peptides, and in turn the microorganisms, in unique and important ways.

How do you detect and decipher the products of novel enzymes?

“Mass spectrometry has played a vital role in my research. I use this extremely sensitive technique because the quantities of the molecules available to me are very, very low sometimes, and the modifications are very, very subtle. If you think of amino acids as letters, then mass spectrometry describes each letter present in a peptide, and in which order, so that you can accurately read the word. ”

Synthetic biology is an emergent and multidisciplinary field that involves the engineering of biological molecules. How does your research fit into this discipline?

“I define myself as a Natural Product Biochemist who uses Synthetic Biology to aid my research. It’s my tool rather than my primary research focus.

Synthetic biology has come a long way for DNA or RNA, but for natural products, it’s still in its infancy. You cannot yet easily piece together letters to make any word you would like to have. The biggest problem is being able to systematically build on the information that you do receive, and have it feed back into your understanding, so that you can actually build more and more complex molecules.”

What new information do you want to feed back into the field?

“If you want to study and produce new compounds, and figure out the different languages microbes use, you need to know not only how to manipulate and work with bacteria, but also how to pair particular natural products with particular bacterial models.

I’m interested in developing expression hosts from different genera, orders, and possibly even phyla in order to standardize how we approach bacterial model systems, under a very limited set of conditions, and using specific vectors. With the backdrop of symbiosis, the coup d’état would be to grow a macro-organism essentially as an incubator for other bacteria.”

How could a greater understanding of microbes and the languages they use contribute to new biotechnologies?

“Oh, in many, many ways. For instance, if we learn how microbes talk to each other, then we give ourselves the opportunity to make them listen, so to speak. This could be in the context of our own gut bacteria to improve health or in bioremediation processes, to become more responsible stewards of the planet. Finding new molecules may lead to new pharmaceutical drugs, and new enzymes can always lead to new opportunities in modifying those drugs or other materials. It is an incredibly exciting time for my field of science and I feel very lucky to be a part of it.”