Perspectives: 'Amazingly Fertile Ground'
Two LSI faculty members discuss how their long-standing cross-discipline collaboration has helped their research flourish
Since its doors opened in 2003, the Life Sciences Institute has operated under the conviction that unexpected and transformational discoveries lie at the intersection of disparate disciplines — and the best way to unearth these new discoveries is to convene scientists from across scientific fields in a building where they can take on complex scientific challenges together.
David Sherman joined the budding experiment of the LSI in July 2004, and Janet Smith arrived in January 2005. Before their labs were fully unpacked, the chemist and structural biologist had begun to envision a collaboration that could open new avenues for both of their research programs.
Two decades (and 40 joint publications) later, the two professors reflect on the unique conditions that have enabled their transdisciplinary collaboration to flourish and expand, driving their labs and their scientific fields forward. (Interview edited for length)
You arrived at the LSI within six months of each other, and in less than two years you had published your first scientific paper together. How did this whole collaboration form and become fruitful so quickly?
Janet Smith: I had always been fascinated by the molecular systems that David works on, but I was not familiar with him or his work before joining the LSI. And when I was recruited here, I looked up his work and I thought, “Wow, this is fantastic. I’ve been really interested in these.” I knew there was a lot of structural biology to be done — very few structures were known at the time. I reached out to David before I moved to Ann Arbor, and we met up to chat about the potential. Just in that initial conversation, we realized that this was amazingly fertile ground.
David Sherman: I have the exact memory of our meeting, and just having an electrifying discussion and feeling like this was going to be incredible. Even before I came to Michigan, I had been thinking about the evolution of the field of natural products discovery and how the piece that was still really missing was structural biology. I was confident that I would find someone at Michigan and a great partnership could start, and that’s what happened with Janet. And we quickly launched into a theme that has driven our collaboration for the last 20 years.
How would you describe that theme? What lies at the core of this collaboration?
DS: Well, we study these amazing bacteria that produce complex natural product molecules. Many of them have become FDA-approved drugs. And the way they’re constructed is with these biochemical machines inside microorganisms. These machines have many working parts, like a car engine, and they all have to work together in synchrony. So at a high level, we want to essentially understand the different moving parts in the machine that built the molecule and to understand the details of how the construction occurs. At that time we had the ability to determine what the machine was doing, but we had no structural insights to tell us how it was working.
JS: And it turns out there are a lot of machines that are very similar to each other, but they all make different molecules. So, from my perspective as a lover of protein function and how a protein’s structure enables its function, I’ve been really fascinated by how enzymes that have some standard function get slightly adapted in nature to do some truly unusual chemistry that doesn’t happen elsewhere.
We want to uncover how these reactions take place and how the enzymes can be tweaked to achieve other outcomes. They could be used as tools to do chemistry that is really challenging at the bench, or to create new molecules with important uses — so there’s an application aspect to it. But we’re also interested in it from a fundamental, “how does this protein work?” perspective.
You’ve sustained this work for almost 20 years now. What do you think has contributed to the productivity and longevity of the collaboration?
JS: I think it has a lot to do with how we think about problems. I do have a degree in chemistry, but I think in terms of the 3D structure of the enzymes that build these compounds. I approach it from a very protein-centric perspective: How does this protein perform its function, where did it come from, who are its ancestors? Whereas I think David thinks of it from a much more chemical perspective and the discovery of natural products.
DS: Yes, the fundamentals for me are driven by the architecture of the molecules. I can just look at a compound and get an instant sense that there is something unique and exciting happening, and I’ll want to study it. I’m interested in the organic chemistry and the mechanisms of how it all comes together. But the way it comes together is through the enzymes that catalyze these reactions, which Janet studies. You can do all the chemistry without knowing anything about the enzymes, but ultimately you need to actually find the enzymes and run the experiments to assess if they’re working in the way that you’re predicting. That’s what structural biology has enabled.
So our interests fit together in a really important and complementary way. And I think one of the reasons we’ve had such a long, successful period of collaboration is because we can each contribute to the work in unique ways, but we’re also both really interested in the whole picture. And that’s really, in my view, where you want to be with a collaboration.
I love having people in the institute who have very, very different scientific backgrounds. The cross-fertilization and ability to learn from them is really wonderful.
How has your focus evolved over the past two decades? Has it impacted the direction of your research programs or even the broader scientific field?
DS: Our work together has stimulated a lot of further integration of innovative methods that I think other people in the field have really adopted. What Janet’s lab does gives us an amazing snapshot of how a substrate is actually held in an active site and offers insights into the potential mechanism for the reaction. We have this pipeline now: We isolate the molecule and select it as something we’re really interested in, we figure out what the biosynthetic enzymes do, and then we get the structural biology information. And that’s helped us to move into engineering proteins — to coax them to do things they can’t do in nature, to expand their ability to accept unnatural compounds and diversify molecule structures — which is a field that is really exploding now.
JS: And more recently, there have been a lot of advances in computational biology that help us get a much deeper understanding of what we see in the structures. For example, in the paper we just published, we were able to draw on some of the computational work David had previously developed with another collaborator. That combination of calculations, biochemical data and what we saw in the structure allows us to tell a much richer story than we could if we lacked any one of those pieces.