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Chris Wintersinger on New Tools for the Nanoscale Toolbox

The Humans of the Wyss (HOW) series features members of the Wyss community discussing their work, the influences that shape them as scientists, and their collaborations at the Wyss Institute and beyond. 

Chris Wintersinger has always been interested in constructing things – he used to be involved in woodworking, welding, and HVAC systems. Now, working at the nanoscale, he’s building what could be referred to as the wrenches, screwdrivers, and fasteners that will be used to bind nanomaterials together with unprecedented control for more sensitive diagnostics. Learn more about Chris and his work in this month’s Humans of the Wyss.

What are you working on?

I work in biomolecular engineering in Wyss Core Faculty member William Shih’s lab, where I am creating new strategies for linking together smaller monomers into larger assemblies, with unprecedented control over their formation.

We developed DNA slats – a monomer made up of a linear chain of weak DNA binding sites – that we weave together into ribbons using a strategy called crisscross cooperative polymerization. The single binding sites that make up the DNA slats are extremely weak, which ensures that spontaneous growth and assembly are very unlikely. In order for these slats to bond, we must add a biosynthetic “seed.” When a “seed” is added, the DNA slats assemble into a ribbon. The fact that the slats will only bind when there is a “seed” present means we have precise control over the system.

My colleagues and I have shown that this system is effective over a much wider variety of conditions (e.g. salt concentration, temperature) than what competing systems in the field allow. This approach is also generalizable to other materials, such as much larger slats folded from DNA origami. We see crisscross cooperative polymerization as a nanoscale toolbox, providing its users with the wrenches, screwdrivers, and fasteners they need to build novel molecular products.

We see crisscross cooperative polymerization as a nanoscale toolbox, providing its users with the wrenches, screwdrivers, and fasteners they need to build novel molecular products.

Chris Wintersinger

All of the work to-date in crisscross is the basis of my PhD. I’ve been working closely with Dionis Minev and Anastasia Ershova, who are also graduate students in the Shih lab. Dionis and I are co-first authors on the first submitted manuscript on this topic, which is publicly available on bioRxiv.

What real-world problem does this solve?

A generalized cartoon rendering of a ribbon of slats assembled using the seed (light green). Slats only begin to bind once a seed is added, which allows the first series of dark green slats to bind and begin polymerization of periodic sets of blue and gold slats that are added sequentially to the end of the ribbon. Credit: Wyss Institute at Harvard University

The key application of crisscross cooperative polymerization is single molecule detection for diagnostics. Existing state-of-the-art detection tools are not as sensitive because they are subject to background noise, or undesired non-specific molecular interactions, which cause false positives. We foresee using crisscross to detect pathogens in humans with the sensitivity of a single disease marker per milliliter of sample. Such sensitivity could transform diagnostics, allowing clinicians to detect extremely low pathogen loads during the early stages of an infection. Then they can begin aggressive treatment earlier in the disease course, ultimately leading to better patient outcomes.

There are other applications for this system. Crisscross cooperative growth could be used in structural biology, material science, or DNA computing. All of these applications are limited by the tools currently available. Crisscross cooperative polymerization could provide a crucial advance in each of these disciplines because it achieves extreme control over exactly where and when molecular assembly begins, which has previously been challenging to attain.

What inspired you to get into this field?

During my undergraduate career at the University of Calgary, I was studying biomedical science and cancer biology. The most memorable event that really made things click for me was a competition called iGEM, which stands for International Genetically Engineered Machine Competition. It’s an event where a team of undergraduate students from different backgrounds comes together to try to solve a real-world problem using synthetic biology. One year it was engineering microbes to break down toxins in the oil industry; another year it was building a biosensor to monitor dangerous E. coli in the meat industry. This was the first time I really saw the kind of theoretical stuff I was learning in my science courses applied to create things in the real world. That inspired me to apply to bioengineering programs for graduate school.

What are some of the challenges that you face?

One of the biggest challenges is the timespan required to bring a new technology to market. Early on, I’m excited by imagining different ways my PhD could be a vital piece to create better diagnostics. Yet, the deeper I dig, the more I realize how much more work must still happen to achieve that goal.

In the best kind of protein biosensors that are currently being used for diagnostics, we can maybe detect down to tens of thousands of molecules. In our lab, William Shih is challenging us to build a biosensor with zeptomolar sensitivity. That means if you had a milliliter of volume of a sample, we could detect six molecules. Six seems like such a tangible number, but when you think of the scale of a molecular system, detecting six molecules is like trying to find a needle in a haystack the size of Mount Everest. There’s something kind of humbling about that. You can wrap your head around the idea, but the scale is still impressive.

I know there’s a limit to what I can achieve in the finite amount time I have at the Wyss to do this work, but even with those constraints, I’m excited by the work I’m doing and the idea that I’m laying the groundwork for a system with such widespread potential.

What continues to motivate and excite you?

What’s motivating me right now is building better tools to assemble things at the nanoscale. That’s what I wish to achieve in my thesis before I leave the Wyss and move on to the next part of my career. I want to see these ideas of the seed and crisscross assembly and DNA slats generalized to other DNA materials so it could be used for other applications.

I’m also struck by the scale of molecular systems.When I consider that a single microliter of DNA origami reaction which I routinely synthesize in the lab contains billions of folded molecular machines, I’m amazed!

Even though it’s so small, I love that you can actually see it. We’ll build something and then we can look at it under an electron microscope. Having that visual feedback is really exciting. 

How have your previous work and personal experiences shaped your approach to your work today?

When I was in high school, I was kind of a shop kid. I was very interested in my woodworking classes, I enjoyed welding, and I even spent a few years prior to starting my bachelor’s degree working in HVAC and refrigeration. I always liked how you started with a problem and then you tried to think of what you could build to solve it. At the University of Calgary, I found that same principle in iGEM. Then, I really found it at the Wyss in William Shih’s lab.

I always liked how you started with a problem and then you tried to think of what you could build to solve it…I really found that same principle at the Wyss in William Shih’s lab.

In the Shih lab, we’re trying to use structural DNA nanotechnology to solve hard problems. That can be anything from trying to build more sensitive biosensors, to trying to build new tools for structural biology, to building new therapeutics. DNA is analogous to some aspects of my old life working with wood and HVAC systems. It’s a material that’s easy to control. You can use it to build virtually any 3D object. You can functionalize it. It has clear design rules. We can sketch out these complex nanomachines, design them, test them, build them at the bench, and if they don’t work, we can reopen the design and start the process over. 

When not at the Wyss, how do you like to spend your time?

A big part of my life now is cooking. It follows the same theme of working with my hands to create something. I love to explore new recipes and try different cuisines. The latest thing I’ve been toying around with is yogurt making. I want to learn the mystery behind that process; I’m seeing how different microbes affect the taste of yogurt. You can go to the supermarket and buy something on the shelf, but if you make it yourself you really get to understand it. Something else I really like about cooking is that no matter how my day goes in the lab, no matter what else happens, I can always control what I’m eating. I can depend on knowing that I can come home and make a meal happen in a relatively short period of time.

Another hobby of mine is scrambling and hiking. I’m a bit less in touch with that here in Boston, but I grew up in Calgary, Canada, which is really close to the Rocky Mountains. Hiking lets you see the world in a different way. There’s something about being on top of a mountain that gives you a new perspective.

Family is also important to me and my girlfriend. Though ours is far away in Texas and Canada, we take weekend trips to see them as often as we can. It’s great to stay connected to the others in our life that matter.

If you had to choose an entirely different career path, what would it be?

I’d be really interested in pursuing environmental protection or environmental justice in some way. It’s a big, beautiful world and I want to help keep it that way. This problem can be very challenging because there are so many variables that impact the health of our planet in a variety of ways.

I’ve also thought about being an explorer. I know they don’t really exist in the traditional sense anymore, but I’m the type of person that will Google something, like a tiny island, and want to know more about it and go see it. I get to do some of that with scrambling and hiking, but I think there is so much more out there to see.

What does it feel like to be working on cutting-edge technology that has the potential to have a real and significant impact on people’s lives and society?

It takes time and a team of people to get something out into the world that’s truly transformational. That’s something I love about the Wyss Institute – there are so many resources here.

Chris Wintersinger

It feels exciting, but at the same time it also feels daunting, because I don’t believe the sort of technologies that are going to make a huge impact on somebody’s life will be invented by just one person overnight. It takes time and a team of people to get something out into the world that’s truly transformational. That’s something I love about the Wyss Institute – there are so many resources here. Even though the road I’m on may look long right now, I know that this technology will continue to mature through the pipeline towards commercialization, and once it’s developed to the point where it can have a positive impact on the world, there are people at the Wyss with the expertise to make it happen.

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