Yale West Campus @10: DNA origami - In conversation with Chenxiang Lin

This fall Yale marks the 10-year anniversary of the purchase of its West Campus. In this series of highlights, we feature the work of faculty, students and staff, and ask about their experiences and what drew them here.

Chenxiang Lin is an assistant professor of cell biology and has been a faculty member at the West Campus Nanobiology Institute since 2012. The Institute focuses on the discovery of principles that unite living and synthetic materials at the nanoscale - usually measured in nanometers, equal to one billionth of a meter. Researchers explore synthetic cellular nano-machines as a means to mimic complex biological assemblies.

Lin’s research manipulates DNA like a building material, creating scaffolds and hoops that are found nowhere in nature but that make possible a new realm of cell biology experiments.

Tell us more about these DNA structures and why you’re building them.

Instead of treating DNA as a genetic carrier, we treat it as a building block. Based on a few simple motifs to make branched DNA structures, you can make multiple pieces of DNA come together to form complex weaves like 2-D and 3-D origami. It’s a simple concept that Ned Seeman at NYU came up with 30 years ago. The structures are usually made of bundles of double helices – that’s what gives them rigidity. It’s a technique for us to control molecular shapes, and shape is important in cell biology.

If we have a way to program shape in a test tube, we get to mimic the elegance of nature and start to understand it.

On the structure we build, the whole surface is made of DNA with unique sequences everywhere – this point is different from that point; this guy’s neighbor is different from that guy’s neighbor. What DNA allows us to do is to chemically modify certain bases and use those bases as anchor points to grab other guest molecules. We get to place our molecules of interest in a very specific way. That starts to get interesting. We can control, for example, the distance of different proteins and see how close they are in order for them to start biomolecular interactions.

This technique allows us to ask specific, fundamental questions in biology that are otherwise hard to answer inside a cell.

What kinds of questions?

The strong suit of cell biology is membrane trafficking – membranes inside the cell constantly change their shapes as they go from one compartment to another delivering things. There are a bunch of known proteins that help membranes keep and change their shapes, and people know what those proteins are and have made hypotheses about how exactly they work.

But there are certain details that are hard to delineate within cells, so that’s where we come in. We make very specific membrane constructs to help study those questions in a test tube. The goal of this project is to create artificial but well-controlled membrane shapes on DNA templates.

So what you make is, essentially, a DNA scaffold with the membrane draped over it?

That’s basically the idea–we either coat the surface of the DNA structure, or we blow a bubble inside to create vesicles or liposomes. Now we have a way to control, arbitrarily but precisely, the membrane shape.

You’ve published twice recently in Nature Chemistry. What did you describe in those papers?

In last year’s paper, we started with a template of DNA rings and grew a spherical liposome inside. The construct looked like Saturn. After that, we started getting more ambitious. Can we deviate from spheres and make something more close to the shape of membranes found in cells? On top of that, can we make dynamic membrane structures? In this year’s paper, we reported these breakthroughs.

What we hope to do in the near term is use those membrane shapes to better understand how membrane proteins interact. In the longer term, we hope to take advantage of our engineering power and build biomimetic devices that we can incorporate into our artificial membrane compartments. With two other principal investigators in the Cell Biology department – Patrick Lusk and Thomas Melia – we’re trying to build artificial nuclear pore complexes. Those are, in nature, massive protein complexes that control what goes in and what comes out of the cell nucleus.

Why Yale, and why West Campus?

What in this environment is most appealing to me is the expertise and strength of my colleagues. At the time I came to the cell biology department for my interview, I had no idea that these DNA nanostructures can be used for so many aspects of cell biological study. During my interview visit, Patrick Lusk grabbed me and said “We’ve got to make a nuclear pore complex together.” We chatted in his office for an hour and then we wrote a grant the first year. And I started collaborating with Jim Rothman before I came here. Jim got interested in using DNA nanotechnology to study membrane fusion, and when I got here, we continued to collaborate. I also work with Pietro De Camilli, the chair of neuroscience, using membrane shapes to study proteins that work between membrane contact sites. And I collaborate with Farren Isaacs of the Systems Biology Institute. His lab comes up with ways of modifying protein with non-natural amino acids. That gives us a nice handle on the protein where we can use it to modify a piece of DNA. This list goes on…

Is it helpful to be part of an institute, with its open-plan labs, to be able to do this type of work?

Definitely - it provides a very good infrastructure. What it means is that there’s no hard boundary. It’s much easier for people in labs to actually talk to each other and share central equipment. For example, we don’t know how to spin down liters of E. coli and harvest proteins from them, but Jim Rothman’s lab does that all the time, so we just take our cultured cells over to them. It makes a big difference. Collaborations start that way.

What can West Campus do to keep nurturing these groundbreaking collaborations?

West Campus is already doing a very good job fostering intellectual exchange and facilitating the collaboration between labs. There are various seminars and symposia happening in different institutes, and across the institutes. The way the institutes are organized, the investigators come from different departments, meaning they have diverse expertise. For example, in the Nanobiology Institute we have a few scientists from cell biology, but we also have Erdem Karatekin from the physiology department, and Julian Berro is from molecular biophysics and biochemistry. The same is true for many other institutes.

Why should doctoral students consider West Campus?

This is a good place to do a PhD! Lab spaces are open. There is diverse expertise. We have top-of-the-line, state-of-the-art instruments and facilities at the Imaging Core, the Yale Center for Genomic Analysis and the Center for Molecular Discovery. Students get the best of all worlds at Yale – interacting with colleagues from West Campus, Science Hill, the School of Medicine. The opportunities are endless.