In the effort to discover new drugs to treat diseases, one technique is to identify a small molecule that can inhibit the activity of a specific enzyme. Traditional methods use a fluorescent and radioactive label to indirectly observe cell activity. But determining which enzyme to block or activate can require running hundreds of thousands or even a few million tests. That number of permutations makes the process extremely inefficient.
Milan Mrksich, biomedical engineering, has inverted that ratio through a mass spectrometry technique so that his lab can evaluate thousands of candidates in a single experiment. The technique, called SAMDI, allows researchers to directly observe a change, caused by a specific enzyme, in the structure and weight of a peptide.
His laboratory has shown how plates having an array of thousands of peptides can be used to measure enzyme activities that are present in a cell lysate. “This means that you can determine in advance whether a given cancer is caused by enzymes that can be targeted with one drug or another, and these studies may lead one to identify a new enzyme target for a drug discovery program,” says Mrksich, the Henry Wade Rodgers Professor in Biomedical Engineering, Chemistry, and Cell and Molecular Biology. “It also allows us to design surfaces that help us understand how cells communicate with their immediate environments; for instance, so that a liver cell knows it’s in a liver environment.”
Mrksich, co-director of Northwestern’s newly launched Center for Synthetic Biology, says cell biology serves as a research foundation. “All our work starts with a good understanding of the cell biology, then designing surfaces that are biologically active,” he says. “That’s a real mix of chemistry, materials, and biology.”
Mrksich’s multidisciplinary approach to solving such problems is a result of his lifelong passion for building things. Research News spoke with him to learn more about his professional journey.
What was your earliest research project, invention, or scientific discovery?
I got a chemistry kit when I was about nine. I put together oscillating reactions in a clear solution. After a while, it turned violet, then clear again, then violet. It was an early point where I saw chemistry’s power and complexity.
Why is it important to you to have students in your lab?
As a child, I was inquisitive and looked at the world around me. How did a clock work? A TV screen? An animal? How did a bird fly? That led naturally to a career where I would mix science and engineering: I observed how cells produce molecules, then engineered a tool that allowed me to take what biology gave us and enhance it. What connected my youthful curiosity to my career was the chance to work in a science lab as an undergraduate chemical engineering student. I was the first in my family to go to college, and until I worked in a lab, I had no real idea what scientists did. So it’s important to me to share that experience with other students.
What about your current research most excites you?
At Northwestern, we’ve been working with colleagues to create enzymes that work in concert to convert a simple molecule into a useful target molecule. We might have millions of possible enzyme combinations that can accomplish this transformation, and using SAMDI, we can run a million experiments in a month. That kind of throughput has never been harnessed in synthetic biology. This rapid, high volume testing enables us to see which combinations of enzymes are most effective. In synthetic biology, we can use biology’s methods to make a broad variety of molecules. Some of those are manufactured drugs, but others are high-value chemicals or biofuels. For instance, if you take plant mass, enzymes can convert that plant mass into small molecules that are chemically important.
What breakthroughs may be possible with synthetic biology?
I’m excited about bringing synthetic biology to a point where there’s no longer a question whether a given molecule can be made with a synthetic approach, and where this is a mature technology that anyone can access. That would fundamentally change the manufacturing paradigm. People no longer will think about building a chemical plant to build a molecule; instead, they will build a biology platform. I believe we’ll see that happen over the next 10 to 20 years. That would be such an enormous game-changer about how we make chemicals, therapeutics, and fuels. It would also lead to manufacturing methods that have a low impact environmentally, so we’re not using organic solvents, caustic reagents, and catalysts. Instead, we’re basically using green matter to produce all the things we use.